Supplementary Material for: Proton pump inhibitors and hyporesponsiveness to erythropoiesis stimulating agents in hemodialysis patients: results from the Japan Dialysis Outcomes and Practice Patterns Study

Introduction:
Hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is important problem in dialysis patients. While proton pump inhibitors (PPIs) may inhibit iron absorption, few studies have examined associations between PPIs and ESA-resistant anemia in hemodialysis patients. This study examined the associations between PPIs and ESA-resistant anemia in hemodialysis patients.

Methods:
The present study was a cross-sectional study using repeated 4-month observations, up to eight observations/patient, from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS). The primary outcome was erythropoietin resistance index (ERI). ESA dose, hemoglobin, proportion of erythropoietin-resistant anemia, transferrin saturation (TSAT), and ferritin were also examined. Linear or risk-difference regression models were used with generalized estimating equations to account for repeated measurements.

Results:
Of 1644 patients, 867 patients had PPI prescriptions (52.7%). Patients prescribed PPI had higher ERI, higher ESA dose, and lower TSAT levels. Multivariable analysis for 12,048 four-month observations showed significantly greater ERI in PPI users (adjusted difference 0.95 IU/week/kg/(g/dl) (95% CI 0.40 to 1.50)). Significant differences were also found in ESA dose (336 IU/week (95% CI 70 to 602) and the prevalence of erythropoietin-resistant anemia (3.9% (2.0% to 5.8%)) even after adjusted for TSAT and ferritin. Among possible mediators between the association of PPIs and anemia, TSAT was significantly different between PPI users and non-users (adjusted difference, -0.82% (95% CI, -1.56 to -0.07)).

Conclusions
This study showed the associations between PPI and ERI, ESA dose, and TSAT in hemodialysis patients; physicians should consider anemia’s associations with PPIs in hemodialysis patients.