A Possible Reason for ESA Resistance
Jula K. Inrig, MD
SAN DIEGO—Researchers have found evidence that could help explain why some anemic CKD patients are resistant to treatment with an erythropoiesis stimulating agents (ESA).
Jula K. Inrig, MD, MPH, Assistant Professor of Medicine at the University of Texas Southwestern Medical Center in Dallas, and collaborators studied 32 CKD patients receiving anemia treatment with darbepoetin alpha: 21 who were receiving usual doses (mean 49.7 mcg/week) and 11 who were receiving high doses (94.1 mcg/week). The patients in the two groups had similar baseline characteristics, although the high-dose group had lower three-month average hemoglobin levels.
In adjusted analyses, patients on high-dose ESA had significantly elevated levels of the inflammatory biomarkers C-reactive protein and interleukin-6 as well as higher levels of endogenous soluble erythropoietin receptors (sEpoR). High-dose ESA was not associated with leptin or adiponectin levels.
High ESA dose requirements are associated with adverse clinical outcomes, yet the mechanisms are uncertain, said Dr. Inrig, who reported findings here at the American Society of Nephrology's Renal Week conference.
“Among participants treated with higher doses of ESA, we identified significantly higher levels of inflammatory markers CRP and IL-6, which could be in the causal pathway for adverse outcomes associated with high-dose ESA,” she said. “Whether elevated inflammatory biomarkers are directly caused by higher ESA doses or are simply a marker of a sicker patient population—who require higher doses—remains to be determined.”
Dr. Inrig noted that the study is the first to reveal in vivo a direct relationship between ESA dose and soluble Epo receptor as a potential modulator of erythropoietic response to ESA therapy. Although a recombinant form of sEpoR was shown to act as an antagonist of Epo in in vitro and in vivo studies of Epo-EpoR biology and function, it has not been known whether low levels of endogenous, circulating plasma sEpoR can directly modulate erythropoietic responses to exogenous ESAs. “While our study is the first to identify a significant positive relationship between higher ESA dose and higher sEpoR levels,” Dr. Inrig said, “we did not measure pre-ESA plasma sEpoR levels and therefore cannot determine whether ESA therapy itself may be involved in upregulation of sEpoR level in a dose-dependent manner.”
An alternative possibility is that higher baseline sEpoR levels prior to ESA therapy initiation may predict ESA response and dose requirement, she said. Thus, further studies are needed to characterize the relationship between endogenous sEpoR and ESA responses and to elucidate the physiologic role of sEpoR on regulation and control of erythropoiesis, Dr. Inrig added.
The absence of a relationship between leptin and adiponectin and ESA dose suggests that these factors may not be in the causal pathway between adverse outcomes associated with high-dose ESA, she said.