Download Cardiovascular complications are the major cause of morbidity and

IS RECOMBINANT-HUMAN ERYTHROPOIETIN RESISTANCE
ANOTHER PREDICTOR OF CARDIOVASCULAR DISEASE IN END-STAGE
RENAL FAILURE PATIENTS?
Introduction
Cardiovascular disease (CVD) is the major cause of morbidity and mortality in
patients with end-stage renal failure (ESRF) (1). Traditional (age, gender, hypertension,
diabetes, dyslipidemia) and nontraditional (homocysteine, inflammation, oxidant stress etc)
or emerging risk factors are considered to be the causes of atherosclerotic CVD in this highrisk population (2).
Anemia in ESRF patients is considered to be an independent risk factor for heart
failure upon dialysis initiation, whereas it can also predict the recurrence of heart failure at a
later stage (3). Erythropoietin (EPO) deficiency has been recognized as the main cause of
anemia in ESRF and the introduction of recombinant human erythropoietin (rHuEpo) in the
late 1980s significantly improved its management. Almost 90% of patients receiving rHuEpo
respond to treatment and they achieve target hemoglobin (Hb) levels. Nevertheless, a large
number of patients show “hyporesponsiveness” or “resistance” to rHuEpo.
Resistance to recombinant human Erythropoietin treatment
According to the European Best Practice Guidelines and the US Guidelines resistance
to rHuEpo is defined as inappropriate response to treatment with doses >300 IU/kg/week,
when administered subcutaneously, or >400 IU/kg/week and 450 IU/kg/week, respectively,
when administered intravenously (4, 5). Among causes of hyporesponsiveness to rHuEpo the
most common one is iron deficiency, either functional or absolute. Other conditions involved
in rHuEpo resistance are shown in table 1.
Table 1
Haemopoetic factors deficiency
Iron deficiency (absolute or functional)
Vitamin B12/ folate deficiency
Conditions related to uremia/dialysis
Chronic inflammation
Secondary hyperparathyroidism
Haemolysis
Aluminium toxicity
Inadequate dialysis
Malnutrition
Other
Chronic blood loss
ACE inhibitor or AT1 receptor antagonist therapy
Marrow dysfunction (including multiple myeloma, myelofibrosis)
Infection
Haemoglobinopathies
Antibodies against rHuEpo
Could rHuEpo resistance be related to atherosclerotic CVD in ESRF patients? We consider
that some factors of the former entity are common or related to the later one. We will try to
explore these common factors and the probable pathogenetic mechanisms correlating
atherosclerotic CVD to rHuEpo resistance in ESRF patients.
RHuEpo resistance conditions related to CVD risk
1) Anemia
As mentioned above anemia is directly related to the development of heart failure in
ESRF patients. Anemia is associated with hypoxia, which may lead to left ventricular
hypertrophy, myocardial fibrosis, cardiomyopathy and congestive heart failure (6)
Furthermore, erythrocytes are considered as mobile free radical scavenges, providing not
only oxygen, but antioxidant defense systems (eg enzymes of glutathione synthesis and the
oxidative pentose phosphate pathway, superoxide dismutase, tocophenols, ascorbic acid) and
they are able to reach at any tissue or organ exposed to oxidative stress. In renal failure there
is marked reduction in antioxidant and mobile free radical scavenger capacity, due to reduced
red cells number and lifespan and increased oxidative stress associated with uremia per se,
dialysis procedure and alterations in ATP turnover and neuroaminidase activity (7)
Thus, anemia per se, the rHuEpo major consequence could contribute to cardiovascular
disease and to oxidant stress induction – an emerging CVD risk factor - via antioxidant
defense reduction.
2) I.V. iron supplementation
Iron deficiency is the most common cause of rHuEpo resistance (4) and iron supplementation
is recommended in order to achieve upper limits of ferritin levels in HD patients. In this
population, intestinal iron absorption is reduced even in iron-deficient patients and
intravenous iron (IV) preparations are usually administered.
IV iron supplementation induces oxidative stress, LDL and other molecules oxidation,
endothelial dysfunction and probably hemochromatosis by iron overload. (8) Some studies
have detected a positive correlation between intravenous iron supplementation and oxidative
stress induction. Intravenous iron administration in HD patients has been shown to correlate
with increased protein oxidation and inflammation as assessed by elevated CRP and TNF-α
levels (9). Additionally, a correlation between serum ferritin level and low-density lipoprotein
oxidation has been detected, suggesting that iron could promote lipid peroxidation (8).
Furthermore, iron seems to correlate with endothelial dysfunction possibly through
impairment of nitric oxide activity (8).
Oxidative stress induction and its consequences, nitric oxide activity disturbances and
endothelial dysfunction are factors, which contributes to the initiation and progression of
atherosclerosis.
3) Vitamin B12- Folate - Homocysteine
Homocysteine is a sulfur amino acid whose metabolism depends on Vit B12 and folic acid.
Vitamin B12 and folate levels are often low in patients undergoing HD while homocysteine
is much more increased than in general population (10). Homocysteine, is a potential
independent risk factor for atherosclerosis in the general population. Serum creatinine is a
strong determinant of homocysteine levels (11). High dose folate (5-15 mg) reduces the serum
concentration of homocysteine. Some experimental and clinical studies have detected an
improvement in endothelial function, by reducing homocysteine with folate supplementation
(11). Thus vitamin B12 and folate deficiency via hyperhomocysteinemia are concomitantly
risk factors for rHEpo resistance and CVD appearance.
4) Inflammation – Oxidant stress
Inflammatory indices are increased in ESRF patients; the inflammatory state in these
patients is due to factors related to uremia itself, to dialysis procedure and possibly to comorbidities that they present (atherosclerosis, diabetes, sub-clinical infections, advanced age
etc). Oxidative stress is another factor possibly interrelated to inflammation in HD patients
(12, 13).
Inflammatory cytokines can directly inhibit red cell production by suppressing erythroid
colony-forming units and indirectly by impairing iron availability. The second one can be
mediated through down regulation of transferring receptors in erythroid cells along with
increased expression of lactoferrin receptors, which in turn causes increased iron uptake by
tissue macrophages (14) RhuEpo resistance induced by oxidative stress is possibly mediated
through direct suppression of erythroid progenitor cells, oxidative damage of red blood cells
(RBC) membrane – reducing RBCs survival- increased lipid peroxidation in erythrocytes and
impaired iron availability (14, 15, 16, 17)
It is questionable how EPO interferes with oxidative stress. Some studies have shown
that EPO has antioxidant properties (18, 19, 20, 21) and others that increases the need for
antioxidant treatment due to increased consumption of vitamin E, and this is one of the
adverse effect correlated with high doses, frequently used in rHuEpo resistance (15).
Atherosclerosis is an inflammatory process. Recently, many clinical studies showed that
low-grade inflammation could predict atherosclerotic CVD. The already existed or by IV
iron supplementation or other causes induced inflammation – and oxidant stress - might be a
risk index not only for rHuEpo resistance, but also for atherosclerotic CVD. Furthermore, as
recent experimental studies showed inflammation might be a risk factor (22, 23) rather than
only a risk index for atherosclerosis initiation and progression.
5) Secondary Hyperparathyroidism
Secondary hyperparathyroidism is a common complication of ESRF. An inverse relation
between intact Parathormone (PTH) levels and rHuEpo resistance has been detected in
patients undergoing HD. PTH can directly inhibit erythropoesis via inhibition of EPO
synthesis, bone marrow erythroid progenitor’s suppression and indirectly via marrow fibrosis
(24)
Furthermore, there is evidence that secondary hyperparathyroidism in ESRF patients
correlates with CVD, especially myocardial infarction and congestive heart failure, mediated
through increased intracellular calcium in myocytes, vascular and valvular calcification,
impaired vascular reactivity, and direct toxic effects of PTH on myocardium
(cardiomyopathy, left ventricular hypertrophy and fibrosis) (3,25)
6) Inadequate dialysis
Although recent conclusions from the HEMO study showed that moderately increasing
dialysis adequacy cannot influence morbidity and mortality in HD patients, inadequate
dialysis is identified as an important factor of poor response to rHuEpo (26) in HD patients.
Dialysis dose and frequency are related to the removal of uremic inhibitors of erythropoesis,
whereas bioincompatibility of dialysis membranes plays an important role in anemia and
rHuEpo resistance, independently of dialysis adequacy. (26) Secondly, extracorporeal circuit
correlates with mechanical injury of red cells and haemolysis. On the other hand, dialysis
adequacy is possibly correlated to morbidity and mortality – the cardiovascular one is the
more significant – that HD patients present (27). Additionally, bioincompatible dialysis
membranes have been associated with cardiovascular risk due to increased monocyte
activation and production or release of pro-inflammatory and inflammatory cytokines (27).
Thus it seems also that inadequate dialysis and possibly bioincompatibility is another
common risk factor for rHEpo and cardiovascular morbidity and mortality in HD patients.
7) Malnutrition
Malnutrition is a common problem in ESRF patients. It is a potential rHEpo factor. The
recently described MIA (Malnutrition-Inflammation-Atherosclerosis) syndrome correlates
increased inflammatory to decreased nutritional indexes and atherosclerosis in ESRF
patients. Thus malnutrition and inflammation could be common and interrelated risk factors
both for CVD and rHEpo (28).
Conclusions
Although the hypothesis of the present lecture is paradoxical, literature data seem to confirm
this suggestion. Many causative factors of rHEpo are also CVD risk factors. These later are
the non-traditional or emerging atherosclerotic CVD factors that probably are more
significant for this disease prevalence in populations like ESRF patients than in general
population. Fig 1 summarizes correlations between rHEpo – CVD and causative or risk
factors. An ESRF patient resistant to rHEpo treatment seems to have also a greater risk for
CVD than a responder to this treatment. The cause is the existence of common factors that
could provoke both entities.
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