How does erythropoietin affect blood pressure

Similarly, the incidence of hypertension in zidovudine-treated human immunodeficiency virus—positive anemic patients or among those undergoing cancer chemotherapy is low.

Whether BP tracks with hemoglobin or not remains controversial. In a report, among anemic rats with reduced renal mass, preventing anemia of renal failure with EPO aggravated systemic hypertension [ 12 ].

In contrast, a low-iron diet that maintained hemoglobin at a lower level prevented the development of hypertension, hyperfiltration, glomerulosclerosis and proteinuria [ 12 ]. In more recent animal experiments, hypertension did not track with an increase in hemoglobin [ 13 ]. If EPO is administered to anemic animals with chronic renal failure, but hemoglobin is kept stable by feeding an iron-deficient diet, hypertension still occurs.

In blood vessels harvested from these animals treated with EPO, vasodilatory responses to nitric oxide NO donors were impaired but response to several vasoconstrictors was normal. Among patients on long-term hemodialysis, treatment with iron to increase hemoglobin was not associated with parallel increases in BP [ 14 ].

Human data are similarly inconclusive. Some studies show that although an increase in hemoglobin is dose dependent, an increase in BP is not [ 1 , 15 ]. To understand the hypertensionogenic effects of EPO, consideration of the biology of the EPO receptor expressed in the nonhemopoietic tissues is needed. Mutation of EPO receptor is lethal in utero [ 16 ]. However, EPO receptor null mice can survive simply by expressing the EPO receptor in the hemopoietic tissue only [ 16 ].

Despite the lack of the EPO receptor in the endothelium, heart and brain, these mice, somewhat surprisingly, develop normally. Using genetic engineering to rescue EPO receptor null mice, two groups of mice were created with varying amounts of EPO receptor expressed in the hemopoietic tissue [ 16 ]. However, contrary to expectations, in response to induced anemia the time to peak plasma EPO concentrations was delayed in both groups of mice.

This suggests that the extra-hemopoietic EPO receptor may play an important role in the regulation of plasma EPO concentration. There is substantial evidence that blood vessels express the EPO receptor. Furthermore, antibodies to the extracellular portion of the EPO receptor stained the vascular endothelium of the placenta and the umbilical cord.

Cultured endothelial cells proliferate in response to EPO [ 18 , 19 ]. The ability of human umbilical vein endothelial cells to migrate is also induced by EPO [ 19 ].

A series of studies performed by investigators in Japan among mice expressing EPO receptor in only the hemopoietic tissue demonstrate the importance of EPO receptor expression outside hemopoietic tissue [ 16 ] such as heart, lungs and the limbs [ 21 ]. Experiments in these mice lacking the EPO receptor outside hemopoietic tissue display several cardiac, pulmonary and vascular anomalies as follows: i Following coronary ligation, compared with wild-type mice, there was greater infarct size, due in part to accelerated cardiomyocyte apoptosis [ 22 ].

In response to hypoxia, there was an increased risk of the development of pulmonary hypertension due to reduced mobilization of the endothelium progenitor cells [ 24 ]. Some data suggest that the effects on hemopoiesis and vasoconstriction may be mediated by different epitopes on the EPO molecule [ 26 ].

Furthermore, treatment of the above animals with the EPO binding protein and an antibody to this protein increased hemoglobin but did not change BP. These data suggest that the BP increasing effect of EPO and the hemopoietic effect of the EPO molecule may be mediated by different parts of the same molecule.

EPO can also be engineered by targeting it more specifically to the hemopoietic EPO receptor and reducing its ability to bind to nonhemopoietic tissues [ 27 ]. To selectively target EPO to the hemopoietic tissue, it was tethered to an antibody that specifically binds glycophrin A, which is highly expressed on red blood cells [ 27 ]. Compared with wild-type mice, when this new molecule was given to mice carrying the human glycophorin A gene, the half-life of engineered EPO was prolonged, reticulocyte response was augmented and platelet effects were minimized [ 27 ].

The authors speculate that EPO receptor expression on maturing megakaryocytes may create an off-target prothrombotic state.

In their study, since the total platelet count and reticulated platelets were both reduced in comparison to darbepoietin, the new molecule may reduce the risk of thrombotic side effects.

The mechanisms of EPO-induced hypertension are incompletely understood. Figure 1 summarizes putative mediators and their effects on BP are discussed further.

Putative mechanisms of EPO-induced hypertension through its receptors on the endothelial cells, especially in the setting of CKD, can trigger endothelial dysfunction and vasoconstriction.

NO can also trigger ET-1 release, which itself is a potent vasoconstrictor. Prostanoids are downstream to endothelin and there is a net imbalance favoring vasoconstriction. The effects on the renin—angiotensin system are complex, but in preliminary studies vasoconstriction to angiotensin II is enhanced when patients are given EPO. Similarly, compared with patients not on EPO, vasoconstriction to catecholamines is enhanced when patients are treated with EPO. Additional pathways such as volume excess and other mechanisms discussed in the text are not depicted in the figure.

Among untreated patients with essential hypertension, serum EPO concentration correlates with both systemic vascular resistance and h ambulatory BP [ 28 ]. This has led to speculation that EPO may have direct vasoconstrictive effects. In order to interpret the results of cell culture studies, it is important to compare the plasma concentrations of EPO achieved after a bolus dose in humans with that used in preclinical studies.

A study describing the pharmacokinetics of EPO in hemodialysis patients notes that the peak concentration of EPO when given as an intravenous bolus injection was 0. In the same group demonstrated that intracellular calcium is increased in cultured vascular smooth muscle cells in a dose-dependent manner upon incubation with EPO [ 30 ].

The physiological and clinical relevance of these observations is therefore unclear. In humans, EPO by itself does not appear to have any effect on vasoconstriction. In a double-blind cross-over study in nine hemodialysis patients, Hon et al.

BP was measured every 5 min for 60 min following treatment. Between treatments, no differences were seen [ 31 ]. A study in 41 dialysis patients reported an increase in mean arterial pressure from to mmHg after a single injection [ 32 ]. Although the change was only 2 mmHg, it was reported as significant; without a blinded control group, the likelihood of false discovery is high [ 32 ].

A study used subcutaneous arteries isolated from a gluteal biopsy from 17 patients with Stage 4 CKD [ 33 ]. The response to endothelial-dependent vasodilatation was tested ex vivo by evaluating acetylcholine-induced vasodilatation. However, such higher concentrations are supra-pharmacologic and it is unclear if they have relevance to EPO biology.

Furthermore, the effects of EPO may be mediated via endothelin, because using an endothelin type A receptor antagonist abrograted the effects of EPO [ 33 ]. Rats with reduced renal mass have increased endothelin-1 ET-1 expression in the aorta, mesenteric artery and renal cortex [ 34 , 35 ]. These rats have increased h urinary excretion of ET-1 [ 36 ].

EPO induces release of ET-1 from endothelial cells in culture [ 18 , 37 ]. EPO-treated rats with reduced renal mass have no increase in ET-1 in the mesenteric artery or renal cortex, yet the aortic content of ET-1 is increased [ 39 , 40 ]. This suggests that NO has an important effect on abrogating the expression of ET-1 in large vessels and is an upstream process [ 40 ].

Abrogation of oxidative stress in EPO-treated nephrectomized rats by tempol also reduces tissue levels of ET-1, hypertension and renal injury [ 41 ].

This suggests that oxidative stress is also an upstream process to ETgeneration in the kidney. However, as discussed below, prostanoids may be a downstream mediator of ET-1 induced vasoconstriction. Mice specifically expressing ET-1 in the endothelium, when treated with EPO even without nephrectomy, have an increase in BP, impairment of endothelial function, resistance artery remodeling and aortic inflammation and oxidative stress [ 42 ].

These adverse effects can be blocked with exercise over 8 weeks. Consideration of the tissue-specific expression of endothelin receptors is needed to appreciate the endothelin biology. Rats with reduced renal mass have reduced expression of the vasodilatory endothelin receptor type B ET B in the aorta, mesenteric artery and renal cortex [ 34 , 35 ].

This parallels the increase in ET B receptor density in the endothelium of rats [ 43 ]. In rats with subtotal nephrectomy and EPO-induced hypertension, treatment with a selective ET A receptor antagonist is more effective than placebo in abrogating the increase in BP [ 44 ]. In a cross-sectional study of 44 end-stage renal disease patients [24 hemodialysis, 20 continuous ambulatory peritoneal dialysis CAPD ], of which half were on EPO therapy, plasma ET-1 concentration directly correlated with systolic BP [ 49 ].

This correlation is not seen in those not treated with EPO [ 50 ]. Reduced expression of the vasodilatory ET B receptor due to genetic heterogeneity or cross talk by other endothelium-derived vasoactive autacoids such as NO, prostanoids and angiotensin II may play an important role in the genesis of EPO-induced hypertension [ 35 ].

Prostanoids play an important role in maintaining vascular tone and renal sodium handling. In a study, rats with reduced renal mass who became anemic and hypertensive as expected also had an increase in vascular and renal concentration of TXA 2 and PGI 2 [ 52 ].

However, the concentration of EPO used to incubate these rings was far beyond the physiological range. An antagonist of thromboxane, ridogrel, abrogated hypertension in EPO-treated animals but did not alter the plasma concentration of ET-1 [ 54 ].

An antagonist of ET-1, ABT, was even more effective than ridogrel in treating hypertension; moreover, it also reduced the concentration of TXB 2 in the aorta [ 54 ]. Thus prostanoids may serve as a downstream mediator of vasoconstriction in response to ET-1 activation.

The imbalance in vasoconstrictor to vasodilatatory prostanoids may lead to a net increase in vascular resistance and therefore hypertension. The use of antiplatelet therapy has been postulated to prevent the development of hypertension among patients treated with EPO [ 55 ]; the mechanism of the antihypertensive effect remains unclear.

NO is a potent endothelium-derived vasodilator and plays an important role in the genesis of hypertension in CKD. NO has important effects on the endothelium, blood vessels, kidneys and BP. Each of the effects are discussed below. In uremia, NO synthesis in the endothelium is blunted. In comparison, symmetric dimethyl arginine SDMA concentrations are unchanged. In rabbit, aortic rings harvested from animals with intact kidneys, acetylcholine-induced vasodilatation, which is dependent upon an intact endothelium, was not blunted when rings were incubated with EPO for 30 min [ 53 ].

In sharp contrast, among rats with reduced renal mass, the release of cyclic guanosine monophosphate cGMP by nitrate donors of aortic rings is augmented. However, this augmentation is blunted when rats were treated with EPO [ 60 ]. The endothelial and inducible NOS protein mass is reduced in these rats regardless of EPO treatment, but when treated with felodipine, the protein mass in the aorta is restored. Thus the presence or absence of renal failure has an important effect on the role of EPO in blood vessels; calcium-channel blockade may have at least partially restored the abnormalities.

Rats with intact renal mass upon treatment with EPO display an increase in renal NO; this is noted by an increase in urinary cGMP [ 61 ] and urinary nitrates [ 62 ]. Rats with reduced renal mass have a reduction in the urinary nitrate excretion rate that is further reduced with EPO treatment [ 63 ].

The endothelial and inducible NOS protein mass is reduced in rats with subtotal nephrectomy regardless of EPO treatment, but when treated with felodipine the protein mass is restored [ 63 ].

Similar findings are seen in rats with intact kidneys treated with EPO [ 64 ]. Similarly, rats with intact kidneys made hypertensive with EPO have increased urinary excretion of nitrites and nitrates [ 65 ]. The renal vasodilatory response to acetylcholine endothelium dependent and sodium nitroprusside endothelium independent are both similar to vehicle-treated rats [ 65 ].

Thus, reduced renal mass is necessary to uncover the effects of EPO. In rats in whom CKD is induced by ligating renal arteries, the restoration of endothelial NOS by gene delivery improves NO release and prevents the development of hypertension [ 66 ]. In rats with reduced renal mass and EPO-induced hypertension, the treatment of hypertension with felodipine partially restores the abnormalities in NO metabolism [ 63 ]. The critical importance of NO in EPO-induced hypertension has been studied in a transgenic mouse model [ 67 ].

Transgenic mice overexpressing human EPO were generated. Administration of L-NAME led to vasoconstriction, an increase in vascular resistance, hypertension and death of transgenic mice; the wild-type siblings developed hypertension but did not show increased mortality. A translational research study elucidated the mechanism of endothelial dysfunction in 56 patients on hemodialysis treated with EPO [ 68 ].

Endothelial progenitor cells, which the investigators state reflect endothelial cell function, were isolated from these patients and mRNA levels for both the full EPO receptor and a spliced, truncated EPO receptor were measured. The authors note that activation of the full EPO receptor triggers a signaling cascade that ultimately terminates in cGMP and NO production and subsequent vasodilation.

However, it was observed that in patients with EPO-induced hypertension there was a positive correlation with the spliced, truncated variant of the receptor. At least there is some evidence for a reduction in NO generation and blunting of the NO effect on both the kidneys and vasculature.

Transgenic models demonstrate that endothelial NO appears to be critical in maintaining normotension, preventing cardiovascular dysfunction and survival in vivo in the setting of EPO use. In rabbit, aortic rings incubated with very high EPO concentrations result in increased vasoconstriction when exposed to norepinephrine [ 37 , 53 ].

Norepinephrine concentrations were increased following 12 weeks of EPO treatment in one study [ 69 ] but decreased in another study of Japanese hemodialysis patients [ 70 ].

Vasoconstriction induced by infusion of norepinephrine was increased in patients with CKD after treatment with EPO, thus the vascular sensitivity to norepinephrine was increased in human studies [ 51 , 71 ].

In summary, these data suggest both an elevation of catecholamines as well as enhanced sensitivity to catecholamines on the blood vessels as a mechanism of EPO-induced hypertension.

Eggena et al. In the heart, no alterations in mRNAs were seen. In both the aorta and kidney, a significant correlation was observed between angiotensinogen mRNA and BP. In cultured rat vascular smooth muscle cells, Barrett et al. Among hemodialysis patients, infusion of angiotensin II leads to excess vasoconstriction, suggesting that angiotensin II sensitivity is increased with EPO treatment [ 51 ].

These data suggest that the vasoconstrictive potential is enhanced with EPO treatment. This is in sharp contrast to normal human volunteers where EPO treatment caused a reduction in plasma volume, plasma renin activity and aldosterone [ 76 ]. This is because the reduction in systolic BP was similar when rats were treated with traditional triple therapy reserpine, hydralazine and hydrochlorothiazide or with the RAAS blockers captopril or losartan [ 36 ].

Despite an increase in mean arterial pressure in 12 Japanese hemodialysis patients treated with EPO, plasma renin activity was found to be reduced [ 70 ].

Among dialysis patients treated with EPO, a close relationship is seen between exchangeable sodium, an increase in plasma aldosterone and an increase in BP [ 77 ]. As discussed above, attention to dry weight can abrogate EPO-induced hypertension among dialysis patients. The above data—both in animals and humans—do not exclude the possibility of EPO causing hypertension by inducing volume excess or in the setting of volume excess. For example, the rodent subtotal nephrectomy models are associated with volume overload, which may be a prerequisite for developing hypertension.

EPO, as noted above, can provoke sodium retention as well. However, the quality of the data do not allow deducing a cause-and-effect relationship. Blood viscosity increases in parallel with blood hematocrit and has been cited as a mechanism of EPO-induced hypertension. However, not all patients who have correction of anemia get hypertensive. Thus the change in blood viscosity by itself appears to be insufficient to account for EPO-induced hypertension.

Thus the vascular response to hypoxia—and its reversal with correction of anemia—may be a fundamental mechanism of the genesis of hypertension induced by EPO. Inhibitors of prolyl hydroxylases can stabilize HIFs, simulate hypoxia and promote erythropoiesis [ 79 ]. HIF stablizers not only stimulate EPO, but also many other genes responsible for angiogenesis, tumor growth, cell proliferation and metabolism.

HIF stablizers may aggravate hypertension by several mechanisms. For example, chronic intermittent hypoxia through HIF signaling in the carotid artery is thought to provoke systemic hypertension [ 79 ]. A study in in vitro and in vivo rodent models shows that hypoxia induces inorganic phosphorus—induced vascular smooth muscle calcification [ 80 ].

In this rodent model, roxadustat, an oral HIF prolyl hydroxylase inhibitor, enhanced vascular calcification [ 80 ]. The downstream effect of long-term use may therefore be hypertension. Vascular calcification is common in CKD and contributes to arterial stiffness. Increased arterial stiffness is strongly associated with elevated interdialytic ambulatory blood pressure [ 81 ].

A study demonstrated that compared with EPO, treatment with the HIF stabilizer molidustat corrected anemia associated with subtotal nephrectomy, but in contrast to EPO, it reduced systolic BP in a dose-dependent manner [ 82 ].

The authors postulate that anti-inflammatory and antifibrotic effects of the drug on the kidney may be operative. Elevated BP is not related to dose of rHuEPO, nor to the final hematocrit level achieved or the rate of increase of hematocrit. Increases in BP arise particularly during the first 4 months of therapy, and BP usually stabilizes thereafter. The mechanism of hypertension related to rHuEPO remains uncertain.

An increase in systemic vascular resistance occurs in all patients, whether or not BP increases. This is due largely to increased blood viscosity and reversal of hypoxic vasodilatation, but other factors may also contribute. Last Update Posted : February 5, See Contacts and Locations. Study Description. The investigators hypothesize that compared to untreated controls, erythropoietin EPO therapy in anemic patients with chronic kidney disease will raise diastolic blood pressure BP.

The magnitude of increase in diastolic BP at 12 weeks after treatment will be related to two factors. First, endothelial dysfunction and worsening of endothelial function from baseline to 4 weeks and second, the change of forearm blood flow in response to breathing oxygen and the change in this measure from baseline to 4 weeks.

Study procedures include fasting blood draws, ambulatory blood pressure, urine collection, and forearm blood flow tests. The study hopes to accrue subjects. Detailed Description:. Hypertension is a common but frequently overlooked and underreported adverse effect of erythropoietin EPO therapy.

Recent trials have noted substantial cardiovascular risks associated with normalization of hemoglobin. The risk of strokes is strongly related to poorly controlled hypertension.

Blood pressure was not measured the way it usually is in hypertension trials, so the investigators cannot be completely confident that the risk of strokes in this large randomized trial was not related to EPO-induced hypertension.

New therapies, such as hypoxia-inducible factor HIF stabilizers are on the horizon but it remains to be seen whether these new drugs would have a lower or a higher risk for hypertension compared to EPO.

Accordingly, understanding the mechanism of EPO-induced hypertension is urgent. The investigators hypothesize that compared to untreated controls, EPO therapy in anemic patients with chronic kidney disease CKD will raise diastolic blood pressure. First, endothelial dysfunction and worsening of endothelial function from baseline to 4 weeks and second, the modulation of forearm blood flow in response to breathing oxygen and the change in this measure from baseline to 4 weeks. If the investigators understood the time course, the magnitude, and the mechanisms of exercise-induced hypertension EIH the investigators will better be able to design studies to compare the vascular effects of EPO and HIF stabilizers in the future.

Thus, this study has the potential of improving the investigators' understanding of a common side effect of EPO by precisely quantifying the magnitude of BP change, its effects on endothelial function, and discovering the biomarkers of these adverse effects.

This study is innovative because it will focus on the potential mechanisms by which EPO induces an increase in BP. The time-course and magnitude of change in BP will be assessed using the gold-standard measurement of 24 hour ambulatory BP recordings.

The more frequent clinic BP recordings using validated methods will better allow us to track changes in BP over time. The investigators' lab is uniquely qualified to carry out these experiments due to a large experience with such types of studies. The investigators will examine endothelial function using a reference method -- that of flow-mediated dilatation -- which is established in the investigators' laboratory. The investigators will directly test the hypothesis whether hypoxia-sensitivity of the vascular tissue is responsible for the BP increase.

Drug Information available for: Darbepoetin Alfa. FDA Resources. Arms and Interventions. Used to treat anemia. Participants given study drugs 12 weeks after randomization.

Outcome Measures.