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. This study further illustrates that increases in hematocrit can be dissociated from an increases in blood pressure. The ongoing Phase 3 trials of HIF stabilizers are evaluating, among patients with CKD, the equivalence of hemoglobin increase from baseline compared with approved EPO-stimulating agents.
Whereas hypertension is not a primary outcome measure for these Phase 3 trials, the equivalence of the cardiovascular outcomes is an important safety endpoint.
Human data are available but are inadequate to address the question of hypertension with HIF stablizers. Among patients with CKD not on dialysis who were treated with roxadustat for 16—24 weeks in varying doses, hypertension was reported in 11 7. In the above studies, there was no placebo group or a group treated with EPO alone, therefore, whether the drug is equivalent to, safer or more detrimental than EPO or placebo with respect to hypertension remains unclear.
In summary, mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates hypertension due to EPO, especially in the setting of CKD. Besides the direct effects of the prostanoids, endothelins and NO pathways, EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II and mitigation of hypoxia-induced vasodilatation responses. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in BP by simply treating the animals with EPO binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP.
However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in people with CKD, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that HIF stablizers may provoke hypertension and those with high phosphorus concentrations and sleep apnea may be at an increased risk.
Whether this class of drugs will reduce the risk of hypertension compared with EPO remains to be seen. Blood pressure in hemodialysis patients during amelioration of anemia with erythropoietin. J Am Soc Nephrol ; 2 : — Google Scholar. Effect of recombinant human erythropoietin therapy on ambulatory blood pressure and heart rate in chronic hemodialysis patients.
Nephrol Dial Transplant ; 7 : 45 — Effect of recombinant human erythropoietin therapy on blood pressure in hemodialysis patients. Canadian Erythropoietin Study Group. Am J Nephrol ; 11 : 23 — The long-term effects of recombinant human erythropoietin on the cardiovascular system. Clin Nephrol ; 38 : S98 — S Effect of recombinant human erythropoietin therapy on ambulatory blood pressure in normotensive and in untreated borderline hypertensive hemodialysis patients.
Am J Hypertens ; 8 : — Krapf R , Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis-stimulating agents ESA. Clin J Am Soc Nephrol ; 4 : — Effects of normal hematocrit on ambulatory blood pressure in epoetin-treated hemodialysis patients with cardiac disease.
Kidney Int ; 56 : — Normalization of hematocrit in hemodialysis patients with cardiac disease does not increase blood pressure. Ren Fail ; 22 : — Salem MM. Hypertension in the hemodialysis population: a survey of patients. Am J Kidney Dis ; 26 : — Uraemia is necessary for erythropoietin-induced hypertension in rats. Clin Exp Pharmacol Physiol ; 22 : — Uremia enhances the blood pressure response to erythropoietin.
Clin Exp Hypertens ; 19 : — Anemia lessens and its prevention with recombinant human erythropoietin worsens glomerular injury and hypertension in rats with reduced renal mass. Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure.
Am J Physiol ; : E — E Effect of erythrocyte mass on arterial blood pressure in dialysis patients receiving maintenance erythropoietin therapy. J Am Soc Nephrol ; 4 : — Hypertension following erythropoietin therapy in anemic hemodialysis patients.
Am J Hypertens ; 3 : — Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood ; : — Erythropoietin receptor mRNA expression in human endothelial cells. Recombinant human erythropoietin rHuEPO increases endothelin-1 release by endothelial cells. Kidney Int ; 43 : — Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Nielsen OJ. Pharmacokinetics of recombinant human erythropoietin in chronic haemodialysis patients.
Pharmacol Toxicol ; 66 : 83 — Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target. Tohoku J Exp Med ; : 83 — Cardiovasc Res ; 71 : — Protective role of endogenous erythropoietin system in nonhematopoietic cells against pressure overload-induced left ventricular dysfunction in mice. Circulation ; : — Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice.
Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res ; : — Prevention of erythropoietin-associated hypertension.
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Kidney Int ; 39 : — Erythropoietin increases cytosolic free calcium concentration in vascular smooth muscle cells. Cardiovasc Res ; 27 : — Lack of a fast-acting effect of erythropoietin on arterial blood pressure and endothelin level. Artif Organs ; 19 : — Blood pressure response to erythropoietin injection in hemodialysis and predialysis patients. Hypertens Res ; 27 : 79 — Effects of recombinant human erythropoietin on resistance artery endothelial function in stage 4 chronic kidney disease.
J Am Heart Assoc ; 2 : e Clin Exp Hypertens ; 32 : 61 — Lariviere R , Lebel M. Endothelin-1 in chronic renal failure and hypertension. Can J Physiol Pharmacol ; 81 : — Antihypertensive and renal protective effects of renin-angiotensin system blockade in uremic rats treated with erythropoietin. Am J Hypertens ; 19 : — Recombinant human erythropoietin enhances vasoconstrictor tone via endothelin-1 and constrictor prostanoids.
Kidney Int ; 50 : — Erythropoietin-induced hypertension in rat is not mediated by alterations of plasma endothelin, vasopressin, or atrial natriuretic peptide levels. J Am Soc Nephrol ; 8 : — Plasma and blood vessel endothelin-1 concentrations in hypertensive uremic rats treated with erythropoietin.
Clin Exp Hypertens ; 20 : — Chronic nitric oxide inhibition aggravates hypertension in erythropoietin-treated renal failure rats. Clin Exp Hypertens ; 22 : — Role of oxidative stress in erythropoietin-induced hypertension in uremic rats. Am J Hypertens ; 23 : — Erythropoietin-induced hypertension and vascular injury in mice overexpressing human endothelin exercise attenuated hypertension, oxidative stress, inflammation and immune response.
J Hypertens ; 32 : — Am J Hypertens ; 21 : — Differential effects of endothelin-1 antagonists on erythropoietin-induced hypertension in renal failure. J Am Soc Nephrol ; 10 : — Changes in the alpha adrenergic system and increase in blood pressure with recombinant human erythropoietin rHuEpo therapy for renal anemia. Clin Invest Med ; 14 : — Plasma concentrations of immunoreactive-endothelin in patients with chronic renal failure treated with recombinant human erythropoietin.
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Cyclooxygenase inhibition with acetylsalicylic acid unmasks a role for prostacyclin in erythropoietin-induced hypertension in uremic rats. Can J Physiol Pharmacol ; 83 : — Endothelin release and shift in prostaglandin balance are involved in the modulation of vascular tone by recombinant erythropoietin. J Cardiovasc Pharmacol ; 20 : S25 — S Relationship between eicosanoids and endothelin-1 in the pathogenesis of erythropoietin-induced hypertension in uremic rats.
There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure BP by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP.
However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce hypertension by provoking calcification and augmenting chronic intermittent hypoxia as occurs in sleep apnea.
Others show that there may be an antihypertensive effect via kidney repair. As shown in Figs. Hematocrit and hemoglobin concentrations were significantly higher in the erythropoietin treated animals than in control rats Fig. These hematologic effects were equal in normotensive and hypertensive rats, and they were not modified by the concomitant administration of the angiotensin converting enzyme inhibitor. Although data were collected every week, values shown in Table 2 refer to four measurements being representative of the whole time course.
Subsequently, arterial pressure increased in both groups of animals slightly but not significantly. At no time were significant differences in systolic arterial pressure between control and erythropoietin groups observed. After the second week erythropoietin treatment caused a progressive increase in urinary albumin excretion so that, after 6 weeks of treatment, urinary albumin excretion values were significantly larger than basal values.
On the contrary, in the control group, urinary albumin excretion was unchanged or slightly decreased during the 6 weeks of treatment. Furthermore, after the second week of treatment, urinary albumin excretion of the erythropoietin-treated group was significantly larger than urinary albumin excretion of the control group. During the following weeks, systolic arterial pressure slightly, but not significantly, increased in the SHR-VEH group. In the SHR-EPO group systolic blood pressure markedly increased, and it became significantly higher than blood pressure of the control group after the second week of treatment with erythropoietin.
In the SHR-VEH group, during the 6 weeks of the experimental period, urinary albumin excretion slightly increased and it was significantly larger than basal values at the sixth week. In the erythropoietin-treated rats, urinary albumin excretion markedly increased and it was significantly larger than in SHR-VEH rats after the second week of treatment.
During the second week of treatment with the converting enzyme inhibitor, systolic blood pressure of the SHR-ACEi-VEH group significantly decreased and it remained lower than basal values for the whole period of treatment. In animals simultaneously treated with ACEi and erythropoietin, systolic blood pressure progressively increased and, after the second week of treatment, it was significantly higher than in the control group. During the following weeks, in rats treated with ACE only, a slight, but not significant, decrease of urinary albumin excretion was observed.
In the SHR-ACEi-EPO group, the erythropoietin treatment caused a large increase of urinary albumin excretion that was significantly higher than control values after the fourth week of treatment. At the end of the pharmacological treatment, urinary albumin excretion was tenfold higher in the erythropoietin treated than in the control rats.
At least two coronal sections of each kidney were examined nonquantitatively by light microscopy. The examiner was not aware of the strain or treatment of the rat. No differences were detected in the number of lesions between control and erythropoietin treated rats in either the SHR or WKY groups.
In spontaneously hypertensive rats, treated or not with ACEi, the administration of erythropoietin caused an increase of both the systolic arterial pressure and the urinary albumin excretion. In these animals a significant correlation between systolic arterial pressure and urinary albumin excretion was found Fig.
These experiments show that the erythropoietin treatment elicits an increase in blood pressure in spontaneously hypertensive rats only. Despite similar increases in hematocrit and, therefore, in blood viscosity, arterial pressure does not change in normotensive rats that underwent erythropoietin treatment.
Our data also demonstrate that the erythropoietin administration causes a significant increase in urinary albumin excretion not only in spontaneously hypertensive animals but also in normotensive rats. Our results on the hypertensive effect of erythropoietin are in agreement with pervious data by Susic and associates 25 showing that upward and downward chronic hematocrit changes did increase or decrease blood pressure in hypertensive rats only, whereas the same maneuvers did not affect blood pressure in normotensive rats.
An increase in hematocrit may influence hemodynamics either by a direct effect on blood viscosity, and consequently on total peripheral resistances, or by an indirect effect on local vascular tone, due to an increase of oxygen delivery to tissues resulting from the increased hemoglobin blood concentration. Indeed, an increase in hemoglobin concentration may decreasenitric oxide production from endothelial cells.
The precise mechanism underlying this phenomenon remains unclear. An altered control of arterial pressure may be genetically determined or the consequence of the cardiovascular damage due to the preexisting hypertensive state.
It is also possible that spontaneously hypertensive rats are not able to appropriately decrease cardiac output when peripheral vascular resistances increase. As described in patients who develop pressor response to erythropoietintherapy, 28 spontaneously hypertensive rats might havean increased vascular reactivity to changes in oxygen delivery.
Besides an increase in hematocrit, other mechanisms may be implicated to explain the increase in peripheral vascular resistances following erythropoietin treatment. In an in vitro model it has been suggested that erythropoietin exerts a direct vasopressor effect on isolated proximal resistance vessels of the kidney and mesenteric vasculature 29 ; it was shown also that erythropoietin treatment induces stimulationof endothelin 1. Although it has been suggested that the renin-angiotensin system may contribute to the pathogenesis of the hypertensive effect of erythropoietin administration, 32 , 33 our results do not confirm the possibility that the renin angiotensin system may play an important role in mediating the pressor effect of the erythropoietin administration.
Indeed treatment with an ACEi does not prevent the increase of arterial pressure following erythropoietin treatment. In our experimental conditions, a role of the renin-angiotensin system seems limited to mediate the sodium retention in hypertensive rats, as ACEi treatment significantly increased urinary sodium excretion to a level equal to that observed in normotensive rats.
In addition our data indicate that, a normal renal function does not prevent the increase of blood pressure related to erythropoietin administration.
The increase in urinary albumin excretion, following the erythropoietin treatment, can be the consequence of the concomitant increase in blood pressure, as suggested by the positive correlation between arterial pressure and urinary albumin excretion observed in hypertensive rats.
On the other hand, in normotensive rats treated with erythropoietin no correlation between arterial pressure and urinary albumin excretion was found, because urinary albumin excretion increased in spite of no changes in arterial pressure. Mechanisms other than arterial pressure should be claimed to explain the increased urinary albumin excretion observed in normotensive animals.
As it has been demonstrated that both acute and chronic changes in hematocrit can impair renal and glomerular function, 20 it is likely that the erythropoietin-induced increase in hematocrit may play a role in mediating the increased urinary albumin excretion.
Indeed, a significant correlation between hematocrit and urinary albumin excretion was found at the sixth week of treatment, when all erythropoietin-treated animals both normotensive and hypertensive rats were analyzed data not shown.
Although our experiments do not establish the mechanisms by which an increase in hematocrit promotes albuminuria, a reasonable explanation might be an increase in glomerular pressure secondary to the increased hematocrit. ACEi treatment at a dosage that was effective in preventing the spontaneous increase in arterial pressure and urinary albumin excretion did not modify the proteinuric effect caused by the erythropoietin administration.
This finding suggests that angiotensin II is not the major mechanism mediating the glomerular effect of erythropoietin treatment. Microalbuminuria is considered to be an index of glomerular vascular damage. In conclusion, our results show that the hypertensive effect of erythropoietin treatment, likely mediated by the increased viscosity, is evident in hypertensive rats only. The administration of erythropoietin causes an increase of urinary albumin excretion that is not entirely dependent on the concomitant increase in arterial pressure, both in hypertensive and normotensive rats.
Other mechanisms, such as the increased hematocrit, might explain this side effect. Lancet ; ii : — Google Scholar. Annu Rev Med ; 41 : — Ponticelli C , Casati S : Correction of anemia with recombinant human erythropoietin. Nephron ; 52 : — Am J Nephrol ; 9 : — Raine AEG : Hypertension, blood viscosity, and cardiovascular morbidity in renal failure: implications of erythropoietin therapy.
Lancet ; i : 97 — Ann Inter Med ; : — Am J Kidney Dis ; 14 suppl 1 : 2 — 8. Am J Kidney Dis ; 17 : — Kidney Int ; 38 : —
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