INTRODUCTION — Hypertension is a common adverse effect of erythropoietin treatment among patients with chronic kidney disease (CKD) and even among healthy subjects who receive erythropoietin [1-3]. Hypertension has also been described following the use of other erythropoiesis-stimulating agents (ESAs) in patients with CKD [4]. Among these patients, hypertension may develop de novo or may worsen after introducing ESAs. However, since hypertension in CKD patients may be due to several factors including volume overload, erythropoietin-related hypertension should be a diagnosis of exclusion.
This topic reviews hypertension related to erythropoietin among CKD patients. Other issues related to erythropoietin among CKD patients, including hemoglobin (Hb) targets, are addressed elsewhere:
●(See "Treatment of anemia in nondialysis chronic kidney disease".)
●(See "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)
●(See "Treatment of anemia in patients on dialysis".)
EPIDEMIOLOGY AND RISK FACTORS — Overall, approximately 20 to 30 percent of patients who receive erythropoietin intravenously for the anemia of CKD develop an elevation in diastolic pressure of 10 mmHg or more [5,6]. A phase-III trial involving 251 hemodialysis patients found that 35 percent of patients developed an increase in their diastolic blood pressure (BP) of at least 10 mmHg or required an increase in their antihypertensive agents after three months of ESA therapy. Moreover, 44 percent of patients who were not hypertensive at baseline also had an increase in diastolic BP of at least 10 mmHg, and one-third of them were started on antihypertensive therapy [7].
Much of the evidence that ESAs contribute to hypertension in CKD patients was derived from a series of meta-analyses [6,8]. As an example, in one meta-analysis that included six randomized trials comparing erythropoietin versus placebo or no erythropoietin (n = 387 patients), patients who did not receive erythropoietin had a lower risk of hypertension (relative risk [RR] 0.50, 95% CI 0.33-0.76).
Another meta-analysis from the Cochrane Collaboration that included four controlled trials in nondialysis CKD patients showed a 26 percent higher risk of hypertension in erythropoietin-treated patients compared with no erythropoietin or placebo, but the effect was not statistically significant [9].
A subsequent meta-analysis of the effects of ESA treatment on hypertension, compared with placebo or no treatment, was provided from 24 studies in 9930 participants [4]. The meta-analysis showed that all ESAs increased the odds of hypertension compared with placebo (epoetin alfa odds ratios [OR] 2.31, 95% CI 1.27-4.23; epoetin beta OR 2.57, 95% CI 1.23-5.39; darbepoetin alfa OR 1.83, 95% CI 1.05-3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98-3.92), while the effect of biosimilar ESAs on developing hypertension was less certain [4].
Hypertension was much more common in the early years of ESA use. At that time, the rise in hemoglobin (Hb) was more rapid because of administration of significantly larger doses of ESAs compared with the doses used in current practice [10]. A subsequent meta-analysis has shown a decrease in the hypertensive effects of ESA therapy over time [11].
Risk factors for ESA-associated hypertension — Putative risk factors for ESA-associated hypertension include the following:
●Intravenous administration (versus subcutaneous)
●Hemodialysis versus continuous ambulatory peritoneal dialysis (CAPD) or no dialysis
●Family history of hypertension
●Higher Hb target
●Higher ESA dose
An early report suggested that the BP may be less likely to rise after subcutaneous administration, possibly related to a slower increase in Hb concentration [12]. The magnitude of the BP increase is greater in hemodialysis than in predialysis or CAPD patients [8,13,14]. Hypertension following erythropoietin may be more frequent in patients with a personal or family history of hypertension [15].
The risk of hypertension is increased by targeting higher Hb concentrations. This was suggested by the CREATE study, which reported a greater than 50 percent increase in risk for developing hypertension in patients targeted to a Hb of 13 to 15 g/dL compared with those targeted to 10.5 to 11.5 g/dL [16]. A meta-analysis comprising nine studies, including the CREATE study, also reported a higher risk of poorly controlled BP in patients targeted to higher Hb levels [17]. A meta-analysis that included 27 studies concluded that targeting higher Hb levels with ESA therapy worsens hypertension [11]. (See "Treatment of anemia in patients on dialysis".)
Two factors were thought to be associated with hypertension: the high doses of erythropoietin administered and the rapid rate of increase in Hb concentration. A high ESA dose was associated with increased risk of hypertension in a meta-regression analysis that included 31 randomized, controlled trials [18]. However, the association between ESA dose and hypertension was not significant after adjusting for target Hb concentration [18].
Antiplatelet agents may reduce the risk of erythropoietin-induced hypertension. In one study, for example, the incidence of hypertension after erythropoietin was only 6 percent in patients treated with one of these drugs as compared with 56 percent in those not receiving antiplatelet therapy [19]. Why this might occur is not clear.
PATHOGENESIS — The underlying mechanisms that increase the blood pressure (BP) level in ESA-treated patients remain poorly defined [20]. The effect seems to be independent of ESA effect on red blood cell volume and viscosity. It seems that there are separate epitopes on the erythropoietin protein: One epitope is involved in mediating erythropoiesis, and another mediates the effects on BP increase [21]. Pertinent to this is that erythropoietin receptors are expressed on vascular endothelial cells and smooth muscle cells and thus may facilitate a role for erythropoietin in cellular signal transduction pathways that triggers vasoconstriction and an increase in BP [22]. A consistent finding in experimental and clinical studies is increased systemic and renal vasoconstriction. This effect may be mediated, at least in part, by the direct vasoconstrictor action of erythropoietin on renal resistance vessels [23]. However, multiple other factors may also contribute, including [7,8,15,20,23-33]:
●Enhanced vascular alpha adrenergic sensitivity
●Diminished production of nitric oxide
●Reversal of hypoxia-induced vasodilation after correction of anemia
●Marked increase in cytosolic free calcium levels in vascular smooth muscle cells [34]
●Increased plasma endothelin levels [35-37]
●Arterial remodeling through stimulation of vascular cell growth
●Activation of the renin-angiotensin system
●Elevation of the thromboxane:prostacyclin ratio in vascular tissue
One study, for example, examined the effects of erythropoietin on vascular responsiveness to norepinephrine [24]. Intra-arterial infusions of norepinephrine in anemic patients on hemodialysis caused a decrease in forearm blood flow and an increase in forearm vascular resistance that was significantly less than that found in healthy controls. Repeat studies performed after 6 and 12 weeks of erythropoietin therapy demonstrated that vascular responsiveness to norepinephrine had been restored to values equal to or greater than the control subjects. Mean arterial pressure also significantly increased during erythropoietin therapy. An almost fourfold increase in vasoconstrictor sensitivity to alpha adrenergic stimuli was also evident in the venous circulation of erythropoietin-treated hemodialysis patients compared with healthy subjects, but vasorelaxation in response to bradykinin was unchanged in both groups [32]. Of note, erythropoietin infusion into hand veins of healthy subjects produced no vasoconstriction.
High doses of ESA may limit endothelium-derived nitric oxide (NO) production, which contributes to endothelial dysfunction and hypertension [38,39]. Erythropoietin dose-dependently raised asymmetrical dimethylarginine (an endogenous inhibitor of NO synthase) via downregulation of dimethylarginine dimethylaminohydrolase and lowered NO production in cultured endothelial cells [40].
From a hemodynamic viewpoint, the elevation in BP is consistent with rapid reversal of anemia-induced peripheral vasodilatation with a less than complete reversal of the anemia-induced rise in cardiac output [41]. Why this occurs is not well understood, but impaired myocardial compliance resulting from the cardiac hypertrophy commonly seen in uremia may be an important factor. In older adult patients treated with erythropoietin, the high cardiac output gradually falls over a period of one year and is accompanied by a 25 percent reduction in left ventricular mass [42].
Endothelin is a very potent vasoconstrictor peptide that may play a role in ESA-induced hypertension [35-37]. In a study of 51 maintenance hemodialysis patients, 19 had an increase in BP after eight weeks of treatment with erythropoietin. There was an increase in plasma immunoreactive (IR) endothelin concentrations only in the patients with an increase in mean BP greater than 10 mmHg. The increases in plasma IR-endothelin concentrations correlated with the increase in mean BP [35]. However, other studies have not been able to show upregulation of endothelin in human aortic endothelial cells in response to darbepoetin alfa [43].
Finally, erythropoietin may exert an antinatriuretic effect, likely mediated by angiotensin II, an effect that can contribute to hypertension [44].
CLINICAL PRESENTATION — Hypertension may appear as early as two weeks after initiation of ESA treatment, but its onset may be delayed for four months or more. The increase in blood pressure (BP) is usually mild, but hypertensive crisis with encephalopathy has been reported [45]. (See 'Hypertensive encephalopathy' below.)
At the other end of the spectrum, some chronically hypotensive dialysis patients show an improvement in BP following erythropoietin therapy. However, this does not appear to be associated with a lessening of hemodynamic instability during dialysis [46].
Hypertensive encephalopathy — Hypertensive encephalopathy, sometimes accompanied by seizures, may occur when erythropoietin causes a rapid rise in BP [47]. Hyperperfusion of the cerebral circulation due to a breakdown of cerebral autoregulation may be important in these cases [15]. It is not possible to predict in advance who will develop this complication; as a result, prodromal symptoms (such as persistent headache or visual disturbances) must be looked for, particularly in previously normotensive individuals in the early weeks and months after the institution of erythropoietin therapy.
PREVENTION AND TREATMENT — In patients with pre-existing severe hypertension, we usually delay the administration of ESAs until the blood pressure (BP) is controlled by antihypertensive medications and volume removal. For dialysis patients, we try to achieve the estimated dry weight before starting an ESA. Thus, BP must be closely monitored in all patients with CKD before and during initiation of ESAs.
Therapy of ESA-induced hypertension begins with prevention. The risk of hypertension can be ameliorated by raising the hemoglobin (Hb) slowly [48]. If there has been a rapid rise in the Hb levels, the ESA dose should be reduced.
The risk may also be lessened by aiming for the target Hb levels of 10 to 11 g/dL since targeting higher Hb concentrations has been associated with increased risk of ESA-associated hypertension. (See 'Epidemiology and risk factors' above.)
The use of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHI) may not have the same tendency to cause hypertension. The HIF-mediated transcriptional cascade involves many genes that participate in vasomotor control. The balance between HIF-1 alpha and HIF-2 alpha is critical for the maintenance of systemic arterial pressure and may contribute to a modest BP lowering effect [49]. In a preclinical study, for example, the HIF PHI molidustat resulted in normalization of hypertension in anemic rats with CKD, an effect that was comparable to enalapril [50]. However, in clinical trials, the effect of HIF PHIs on hypertension has been mixed [51-55]. A few of the key trials are discussed elsewhere. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Investigational agents'.)
Patients who remain hypertensive can be treated with fluid removal (via ultrafiltration during dialysis or, if the patient has only CKD, diuretics) and the administration of antihypertensive agents [45]. Any of the conventional antihypertensive agents can be used to control BP, including angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, calcium channel blockers, and vasodilators (see "Overview of hypertension in acute and chronic kidney disease", section on 'Treatment of hypertension in chronic kidney disease' and "Hypertension in dialysis patients", section on 'Treatment'). The dose of ESAs should be reduced or temporarily discontinued for several weeks in severe cases or when other therapeutic measures are ineffective in controlling BP.
SUMMARY AND RECOMMENDATIONS
●Blood pressure (BP) increases of 10 mmHg or more have been noted in 20 to 30 percent of patients who receive intravenous erythropoietin for the anemia of chronic kidney disease (CKD). Subcutaneous erythropoietin administration is less likely to have this effect. (See 'Introduction' above and 'Epidemiology and risk factors' above.)
●The mechanism(s) explaining hypertension resulting from erythropoietin administration is unclear. However, altered vascular responsiveness to circulating vasoconstrictors and vasodilators combined with impaired myocardial compliance are likely participants. Higher targeted hemoglobin (Hb) levels are also associated with poorer BP control. (See 'Pathogenesis' above.)
●Therapy of erythropoiesis-stimulating agent (ESA)-induced hypertension begins with prevention. The risk of hypertension can be ameliorated by raising the Hb slowly. If there has been a rapid rise in the Hb levels, the ESA dose should be reduced. The risk for hypertension may also be lessened by aiming for target levels for Hb of 10 to 11 g/dL. Patients who still remain hypertensive can be treated with fluid removal (via dialysis or, if the patient has only CKD, diuretics) and the administration of antihypertensive agents. The dose of ESA should be reduced or discontinued for several weeks in patients with severe hypertension or when other therapeutic measures are ineffective. (See 'Prevention and treatment' above.)
ACKNOWLEDGMENT — The authors and the editorial staff at UpToDate would like to acknowledge Robert E Cronin, MD, who contributed to earlier versions of this topic review.
