Hypertension following erythropoietin in chronic kidney disease

INTRODUCTION

Approximately 20 to 30 percent of patients who receive erythropoietin (EPO) intravenously for the anemia of chronic kidney disease may develop an elevation in diastolic pressure of 10 mmHg or more [1,2]. In comparison, the blood pressure (BP) is less likely to rise after subcutaneous administration [3].

PATHOGENESIS

How EPO therapy may raise the blood pressure is not well understood [4]. Several factors that may contribute to the hypertensive response have been identified. These include the following [4-17]:

• High dose of EPO
• Prior personal or family history of hypertension
• Diminished production of nitric oxide
• Marked increase in intracytosolic calcium levels
• Enhanced vascular alpha adrenergic sensitivity
• Increased plasma endothelin levels
• 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 upon vascular responsiveness to norepinephrine [5]. Intraarterial 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 [16]. Of note, erythropoietin infusion into hand veins of healthy subjects produced no vasoconstriction.

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. Why this occurs in not well understood, but impaired myocardial compliance resulting from the cardiac hypertrophy commonly seen in uremia may be an important factor. In elderly patients treated with EPO, the high cardiac output gradually falls over a period of one year and is accompanied by a 25 percent reduction in left ventricular mass [18].