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Does Erythropoietin Always Win? V. Cernaro, A. Lacquaniti, A. Buemi, R. Lupica and M. Buemi* Chair of Nephrology, Department of Internal Medicine, University of Messina, Messina, Italy Abstract: The synthesis of recombinant human erythropoietin has marked a turning point in the treatment of anaemia secondary to chronic kidney disease. However, the potentially fatal cardio- and cerebrovascular complications of the intake of high-doses of ESAs (erythropoiesis-stimulating agents), such as those observed in athletes who resort to doping, reason out the ever-prevalent debate concerning the balance between the risks and benefits of ESA administration for therapeutic purposes. Hence, there is still a discussion as to what values haemoglobin should ideally be maintained at. Additional concerns arise in cancer patients due to the ability of erythropoietin to act as an angiogenic and, in general, as a cell growth factor, because this might favour the progression of neoplastic disease. We summarized the prominent points of the latest guidelines on the management of anaemia in nephropathic patients, also identifying the possible risks that may result from the tendency to aim at too low haemoglobin levels.
Keywords: Erythropoietin, erythropoietin receptors, guidelines. PATHOPHYSIOLOGY OF ERYTHROPOIETIN: A LESSON FROM DOPING The world of sport is full of examples of athletes who resort to doping, that is the use (or abuse) of substances or medications in order to artificially increase physical performance. Among the drugs most widely used for this purpose is erythropoietin, a glycoprotein hormone produced in adults mainly by endothelial cells in peritubular interstitial spaces in the kidney in response to hypoxia. The intake of high-doses of ESAs (erythropoiesis-stimulating agents) often leads to a significant increase in haematocrit, resulting in blood hyperviscosity and therefore, potentially fatal cardioand cerebrovascular complications (encephalopathy, stroke, tissue hypoxia, pulmonary embolism, myocardial infarction, sudden death, peripheral clot formation). Even the stimulation of megakaryocytes and the increase in blood pressure caused by erythropoietin contribute to determine these adverse events [1, 2]. Thus, doping is a metaphor of the ever-prevalent debate concerning the balance between the risks and benefits of ESA administration for therapeutic purposes. TISSUE-PROTECTIVE EFFECTS OF ERYTHROPOIETIN ARE QUITE DIFFERENT BETWEEN EXPERIMENTAL MODELS AND HUMANS The fundamental issue lies in the discrepancy between the excellent tissue-protective and regenerative results [3-6] obtained in experimental models and the failure in clinical trials of attempts to use erythropoietin other than for the mere stimulation of the maturation of bone marrow erythroid precursors.
*Address correspondence to this author at the Via Salita Villa Contino, 30 98100 Messina, Italy; Tel: +39.090.2212396; Fax: +39.090.2935162; E-mail:
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It is well known that erythropoietin is involved in the development and maturation of the brain and exerts a neurotrophic and neuroprotective action in experimental conditions of neuronal damage induced by hypoxia, ischemia or cerebral haemorrhage, through anti-apoptotic, angiogenic and neurogenic mechanisms. This seems to be related to the existence of a specific erythropoietin/erythropoietin receptor system in the central nervous system: indeed, erythropoietin and its receptor are expressed by astrocytes and neurons and erythropoietin is present in the cerebrospinal fluid [7, 8]. The beneficial effects of erythropoietin in experimental models of neuronal damage suggest a potential therapeutic use of this hormone in the treatment of brain and spinal cord diseases [9]. The protective properties of erythropoietin have also been documented in the peripheral nervous system of animal models. In 2001, Campana WM and Myers RR [10] demonstrated the presence of both erythropoietin and its receptor in the rat sciatic nerve and observed that in experimental conditions of painful chronic constriction injury, erythropoietin is produced to a greater extent in Schwann cells and appears to stimulate non-differentiated Schwann cell proliferation. Furthermore, it exerts an anti-apoptotic action and prevents axonal degeneration with consequent reduction in limb weakness and neuropathic pain behaviour in an animal model of distal axonopathy; in this mechanism, the signal that stimulates erythropoietin production from periaxonal Schwann cells is nitric oxide [11]. Recently, the focus is shifting to the nonhematopoietic erythropoietin analogue called ARA290, a peptide derived from the tertiary structure of erythropoietin that seems to induce long-term relief of tactile and cold allodynia in rat and mouse models of neuropathic pain because of its antiinflammatory properties, possibly within the central nervous system. Unlike erythropoietin, it activates the -common receptor without exerting haematopoietic and cardiovascular © 2013 Bentham Science Publishers
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side effects; for that reason, it is regarded as a promising new drug in the prevention of peripheral nerve injury-induced neuropathic pain in humans [12]. Similarly, as demonstrated in the rat, erythropoietin has cardioprotective properties in post-ischemic damage. In particular, it acts on cardiomyocytes ultimately resulting in ventricular remodelling, protection against ischemia, and inhibition of apoptosis [3]. Moreover, again in the rat, it has been observed that erythropoietin protects the kidney from ischemia/reperfusion injury slowing the progression of renal failure. The renal protective effects of erythropoietin has been recently demonstrated also in a murine model of acute kidney injury caused by sepsis, through the activation of the -common receptor [13]. These protective effects do not occur to the same extent or as efficiently in humans, in whom, on the contrary, several clinical studies have shown the negative implications of ESA administration, especially at high doses. Indeed, beyond the cardio-and cerebrovascular consequences secondary to the increase in haematocrit, blood pressure and thrombopoiesis induced by the hormone, these trials have highlighted a higher rate of morbidity and mortality in patients treated with high-dose ESAs in the presence of neoplastic disease, because erythropoietin acts as an angiogenic and, in general, as a cell growth factor. In particular, the CHOIR (Correction of Hemogloblin and Outcomes in Renal Insufficiency) study [14], which involved the administration of epoetin alpha, has documented a greater risk of death, myocardial infarction and hospitalization for congestive heart failure in patients with a target of Hb equal to 13.5 g/dl compared to patients in whom researchers aimed at a lower target (11.3 g/dl); in addition, improvement of quality of life was similar in both groups. Again, the TREAT (Trial to Reduce cardiovascular Events with Aranesp® [darbepoetin alpha] Therapy) study [15] has shown a higher mortality in patients with a history of cancer and an increased risk of stroke in patients treated with darbepoetin alpha compared to the placebo group. The difference between the results obtained in humans and those seen in experimental models could be due to the fact that in humans, the effects are observed in vivo and for a time interval greater than those of studies on tissues or animals. For example, high-dose ESA administration, with a resulting rise in cell proliferation in the myocardium associated with increased blood pressure and haematocrit, may cause long-term functional overload and consequently, an earlier "exhaustion" of the organ. Another important issue is the existence of two different kinds of erythropoietin receptors (EPORs): EPOR-2 is located on the surface of erythroid precursor cells and stimulates haematopoiesis; the endothelial receptor, EpoR-CD131, is responsible for tissue regenerative action and has a lower affinity for erythropoietin. Accordingly, different ESA doses are required to activate the two receptors and so obtain the two types of effects (Fig. 1). This has prominent consequences, since erythropoietic doses of ESAs, as the ones used in nephrology, should not induce erythropoietin's pleiotropic actions, which contrariwise must be taken into account in oncology field when high doses of
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ESAs are used in the clinical practice [3]. Anyhow, we must bear in mind that commercially available anti-erythropoietin receptor antibodies may not be suitable for the immunohistochemical detection of erythropoietin receptor, and this can compromise the exact definition of the pleiotropic erythropoietin functions [16]. Probably in the near future, better results will come from further evaluation of the potential therapeutic effects of ARA290, also known as pyroglutamate helix B-surface peptide, that only activates the heteromeric EPOR2-cR2 receptor complex, consisting of two erythropoietin receptors and two beta common receptors, and do not stimulate erythropoiesis [17]. ERYTHROPOIETIN AND CANCER: STILL AN OPEN QUESTION Treatment of cancer- or chemotherapy-related anaemia is a very burning topic. Several studies have been conducted to evaluate whether and to what extent ESAs therapy affects survival and tumour outcomes in cancer patients suffering from anaemia. The results are controversial. Even though some clinical studies have demonstrated that ESAs administration can improve haemoglobin (Hb) levels and quality of life in these patients, also by reducing the need for transfusions, larger randomized controlled trials reported more deaths in patients receiving ESAs, due to an increased risk of thromboembolism, cardiovascular events and cancer progression [18, 19]. Nevertheless, an individual data-based meta-analysis of three randomized, placebo-controlled trials studying Japanese patients with solid tumour or lymphoma and chemotherapy-induced anaemia showed no increase in thromboembolic events and no negative impact on overall survival related to epoetin beta and darbepoetin alfa administration, provided that appropriate patient selection, monitoring of Hb levels and strict dosing adjustment were carried out [20]. It is also important to consider that, in contrast to the numerous reports according to which erythropoietin receptor is expressed in tumours and tumour cell lines [21, 22], very recently Elliott S. and colleagues [23] have demonstrated that erythropoietin receptor is undetectable in human normal and tumour tissues from breast, lung, skin, colon and ovary. This calls into question the hypothesis of a direct action of erythropoietin on cancer cells as a growth factor, even though we must always keep in mind the well established erythropoietin’s angiogenic action and its role in promoting tumour progression and metastases development. Based on these conflicting data, the current thinking and guidelines are going towards a gradual decrease in the target of Hb to be reached in cancer patients, in order to reduce ESA doses required. In addition, it is well known that iron therapy can improve response to ESAs, but some authors suggest the need to evaluate intravenous iron therapy without additional ESA as a potential option to treat chemotherapy-induced anaemia [24]. With regard to this future perspective, a very recent clinical experience has been published concerning the effectiveness and tolerability of ferric carboxymaltose in the treatment of anaemic cancer patients. In this observational
Erythropoietin in CKD
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Fig. (1A). Tertiary structure of Erythropoietin. B) Haematopoietic receptor dimmer (EPOReceptor-2). The tissue-protective effects of erythropoietin appear to require the expression of EPO-R and CD131. C) Erythropoietin concentration, receptors stimulation and tissue effects [3].
study, the intravenous administration of ferric carboxymaltose alone induced a median Hb increase comparable to that of patients treated with ferric carboxymaltose and ESA, with a good tolerability profile [25]. TREATMENT OF ANAEMIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE: GUIDELINES COMPARED Whatever the reason of the different results between human and experimental studies, the data about the side effects of ESA therapy have determined the tendency to progressively reduce the target of Hb in patients with chronic kidney disease (CKD) treated with ESA, in order to limit the dose of drug to be administered. In fact, a few years ago, ESA therapy was usually established when Hb was between 11 and 12 g/dl. On the contrary, the latest FDA recommendations [26] suggest the optimal range of treatment be a Hb concentration of between 9 and 11 g/dl in haemodialysis patients and between 9 and 10 g/dl in patients with CKD not on dialysis, even stating that nephrologists should not exceed the dose of ESA necessary to avoid blood transfusion. The new KDIGO guidelines [27], published in Kidney International in August 2012, partially redefine and better indicate these limits, indicating among other things that: in adult patients with CKD stage V on haemodialysis, ESA
therapy should be started when Hb levels are between 9 and 10 g/dl (Guideline 3.4.3); in adults with CKD but not on haemodialysis with Hb10 g/dl, ESA therapy should not be initiated (Guideline 3.4.1), unless one realizes that quality of life of the subject is better with Hb values above 10 g/dl (Guideline 3.4.4); ESAs should not be used to intentionally increase Hb concentration above 13 g/dl (Guideline 3.6); ESA therapy must be used with great caution, if at all, in CKD patients with active malignancy, a history of stroke or a history of malignancy (Guideline 3.3). Despite the interesting observation that lower Hb values of the patient with CKD would represent a new state of equilibrium of the body and therefore, would not require an aggressive treatment, it is essential in this debate to note that there are no studies on the possible harmful effects of the maintenance of Hb levels at between 11 and 12 g/dl. In addition, the excessive reduction in Hb concentration impairs the quality of life and is harmful to patients with ischemic heart disease because myocardial cells receive less oxygen than their energy needs. Finally, it exposes the risk of having to deal with too weak a boundary between the range of values considered "normal" in CKD and levels that require blood transfusions; aiming at too low a target, the ease with which Hb can considerably decrease may determine relevant consequences if we consider that patients with CKD show a high prevalence of cardiovascular disease.
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So what is the optimal range of Hb to aim for in patients with CKD? Are there also economic reasons behind the tendency to reduce Hb target values? Furthermore, are we to witness a return to blood transfusions in the treatment of our patients? Is it perhaps that we do not remember the problems we had to face when anaemia in renal failure could be treated only with blood transfusions? Think of the difficulty in finding blood units, the necessary treatment for the control of blood, the potential side effects (fever, vomiting, skin rash, transmission of viral hepatitis and AIDS), the risk of sensitization that could adversely affect the opportunity to receive an organ transplant, the possible development of high levels of lymphocytotoxic antibodies that reduce short-term survival of the transplanted organ; all this has both clinical and important economic consequences that must be taken into account. The new KDIGO guidelines concur, suggesting that red cell transfusions be avoided when possible in the treatment of chronic anaemia to minimize the general risks related to their use (Guideline 4.1.1), particularly in patients eligible for organ transplantation because of the risk of allosensitization (Guideline 4.1.2). The benefits of red cell transfusions may outweigh the risks (Guideline 4.1.3) if ESA therapy is ineffective or if ESA administration is harmful because of other clinical conditions (eg., previous or current malignancy, previous stroke). Perhaps due to economic reasons, the mentioned guidelines are more drastic than in Europe, where the proposed recommendations suggest less net restrictions to ESA administration. The European Renal Best Practice (ERBP) group has recently published a position paper where the KDIGO clinical practice guidelines for the management of anaemia in CKD patients are examined in detail and partly adapted to the European population [28]. In addition to emphasizing the importance of iron therapy, already highlighted by KDIGO guidelines although with different limits of serum ferritin and TSAT, the members of ERBP Advisory Board suggest not to consider risk factors for stroke (including a previous stroke) and the presence of active malignancy or a past history of malignancy as absolute contraindications to ESA treatment: they must be taken into account and discussed with the patient, in order to properly balance the risk/benefit ratio of prescribing ESAs. Moreover, they believe that the decision concerning ESA therapy initiation should be individualized, but Hb values should not let be allowed to regularly fall below 10 g/dl in non-dialysis-dependent CKD patients; ESA therapy should not be started if there is a temporary and evident cause of anaemia potentially reversible due for instance to phlogosis, infections, haemorrhages, iron deficiency, or surgical procedures. They also suggest that ESA treatment could be initiated at higher Hb values (no >12 g/dl) in low-risk patients or when quality of life would significantly improve. In high risk patients, such as those with asymptomatic coronary artery disease, ESA therapy should be started when Hb is between 9 and 10 g/dl and Hb level should be maintained at about 10 g/dl. In patients with ischemic heart disease where anaemia induces a worsening of ischemic symptoms, ESA therapy could be initiated at Hb levels higher than 10 g/dl.
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Also with regard to haemodialysis patients, the decision to start ESA therapy should be individualized taking into account the risk/benefit balance, including the risk of transfusions; Hb concentrations should not drop below 10 g/dl; the initiation of ESA therapy could be considered at higher Hb levels but not above 12 g/dl in low-risk patients, in patients with ischemic heart disease and worsening ischemic symptoms due to anaemia, or in those subjects for which an improvement in quality of life can be expected; in high-risk haemodialysis patients, the same recommendations given for high-risk non-dialysis-dependent CKD patients apply. During ESA maintenance therapy, ERBP members suggest to keep Hb values between 10 and 12 g/dl, and to aim towards the lower Hb levels of this range in patients with specific risk factors. Finally, they agree with KDIGO guidelines about the need to avoid red cell transfusions when possible. Also the European Medicines Agency (EMA) express concerns about the association of ESAs therapy with tumour progression, shortened survival, mortality and thromboembolic events. In particular, in a paper published in 2010 [29], the focus is on the need to appropriately define the haemoglobin target levels to be recommended, also stating that there is no guarantee on whether ESA administration can be harmful in both pre-dialysis and on-dialysis CKD patients under the new dosage regimens, especially in those patients suffering from concomitant diseases and presenting other risk factors such as diabetes mellitus. According to the data on tumour progression and shortening of overall survival attributed to erythropoietin in some clinical trials, EMA has also suggested that ESAs should be used in the treatment of anaemia only if symptomatic and established a target Hb range for all epoetins of 10 g/dl to 12 g/dl without exceeding a level of 12 g/dl [30]. Moreover, it has recommended not to administer ESAs in cancer patients with a reasonably long life expectancy; in these cases, blood transfusions should be preferred in the treatment of anaemia [31]. CONCLUSIONS The synthesis of recombinant human erythropoietin has marked a turning point in the treatment of anaemia in nephropathic patients, but once again there is a discussion as to what values Hb should ideally be maintained at. The question is still open and not easily resolved. It is clear that there is a different vital medium between physiological and pathological conditions. In fact, perhaps reserve mechanisms, which allow doped athletes to maintain haematocrit values outside of the norm without side effects, are insufficient in CKD. The complexity of this issue is such that, despite extensive evidence in literature, we have not yet come to a conclusion. The most practicable road appears to be that of compromise and not the trend towards extremely low limits which would expose the patient to the risks that recombinant human erythropoietin has enabled us to avoid, or at least substantially reduce, over the last 28 years. In conclusion, doping is emblematic of the positive actions of erythropoietin and ESAs. The comparison between two populations that are so different from each other (healthy athletes versus CKD patients) exactly serves to emphasize
Erythropoietin in CKD
that erythropoietin is a very effective drug, because it is able to increase red blood cell count and to promote tissue regeneration. Obviously, the administration of an excessive dose of ESAs may be harmful to both populations, but to a greater extent in patients with CKD, because of the presence of comorbidities that make it more difficult to adapt to high haematocrit values with a low risk of complications. In any case, recent cases of doping, regardless of moral issues, have demonstrated that erythropoietin metaphorically "always wins".
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CONFLICT OF INTEREST The author(s) confirm that this article content has no conflicts of interest.
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ACKNOWLEDGEMENTS Declared none.
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Received: January 10, 2013
Revised: July 30, 2013
Accepted: September 06, 2013
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