Erythropoietin-induced hypertension in chronic kidney disease—a mechanistic randomized controlled trial

Background The mechanism of hypertension associated with erythropoietin stimulating agents (ESA) in chronic kidney disease (CKD) is complex and remains poorly understood. Methods Here, anemic hypertensive patients with CKD and well controlled or mildly elevated blood pressure (BP) as confirmed by 24-hour ambulatory BP monitoring were randomly assigned to either a waitlisted group or darbepoetin in a 1:1 ratio stratified by stages of albuminuria. The primary end point was the change in 24-hour diastolic ambulatory BP from baseline to 12 weeks. Results We screened 1699 patients and randomized 27 patients of the planned 160. Mean age (SD) was 75 (8) years, mean hemoglobin 9.4 (0.6) g/dL, mean clinic BP 124.4 (19.5)/57.2 (11.4) mmHg and was similar between groups. At 12 weeks there was 1.7 g/dL (95% CI 0.9 to 2.5 g/dL) difference in hemoglobin between waitlisted and immediate start group. Within group change in diastolic 24-hour ambulatory BP in the waitlisted group was -1.91 mmHg and the immediate start group was +1.07 mmHg. The difference in the changes was 2.98 mmHg (95% CI -1.36 to 7.31), p = 0.18. Comparing systolic BP, endothelial function, and UACR in the waitlisted and immediate start groups showed no significant differences between groups. However, within the waitlisted group UACR increased 35% from baseline (95% CI 11 to 82%) with darbepoetin exposure. Cardiovascular and atherothrombotic serious adverse events were more frequent during darbepoetin exposure. Conclusions Among anemic CKD patients with reasonably controlled hypertension, exposure to darbepoetin did not change 24-hour ambulatory BP or endothelial function. However, increases in albuminuria and serious adverse events during exposure to darbepoetin is a cause for concern and requires larger studies to affirm or refute these observations.