Serum trace metal association with response to erythropoiesis stimulating agents in incident and prevalent hemodialysis patients

Abstract

Alterations in hemodialysis patients' serum trace metals have been documented. Early studies addressing associations levels of serum trace metals with erythropoietic responses and/or hematocrit generated mixed results. These studies were conducted prior to current approaches for erythropoiesis stimulating agent (ESA) drug dosing guidelines or without consideration of inflammation markers (e.g. hepcidin) important for regulation of iron availability. This study sought to determine if the serum trace metal concentrations of incident or chronic hemodialysis patients associated with the observed ESA response variability and with consideration to ESA dose response, hepcidin, and high sensitivity C-reactive protein levels. Inductively-coupled plasma-mass spectrometry was used to measure 14 serum trace metals in 29 incident and 79 prevalent dialysis patients recruited prospectively. We compared these data to three measures of ESA dose response, sex, and dialysis incidence versus dialysis prevalence. Hemoglobin was negatively associated with ESA dose and cadmium while positively associated with antimony, arsenic and lead. ESA dose was negatively associated with achieved hemoglobin and vanadium while positively associated with arsenic. ESA response was positively associated with arsenic. Vanadium, nickel, cadmium, and tin were increased in prevalent patients. Manganese was increased in incident patients. Vanadium, nickel, and arsenic increased with time on dialysis while manganese decreased. Changes in vanadium and manganese were largest and appeared to have some effect on anemia. Incident and prevalent patients' chromium and antimony levels exceeded established accepted upper limits of normal.

Figure 1

Pearson correlation between all measured variables. Red squares represent positive correlations and blue squares represent negative correlations. Asterisk (*) denotes correlation values with a p value < 0.05. Trace metal symbol definitions provided in methods.

Figure 2

Trace metals associated with prior month ESA dose divided into categories: patients that received no ESA and those below and above the median non-zero value. Solid line represents the mean value. Trace metal symbol definitions provided in methods.

Figure 3

Trace metals associated with current Hb divided into categories: below 9.0 g/dL, between 9.0 and 11.0 g/dL and > 11.0 g/dL. Solid line represents the mean value. Trace metal symbol definitions provided in methods.

Figure 4

Trace metals associated with ER divided into categories: 0, did not receive an ESA for 6 months, below and greater than the median non-zero value. Solid line represents the mean value. Trace metal symbol definitions provided in methods.

Figure 5

Dot density plot of the trace metal concentration in prevalent and incident patients with p values. Solid line represents the mean. Trace metal symbol definitions provided in methods.

Figure 6

Comparison of trace metal levels in incident (n = 29) versus prevalent (n = 79) patient plasma samples as a mean fold-difference against literature value for upper limit of normal.