Inflammation, high ferritin, and erythropoietin resistance in indigenous maintenance hemodialysis patients from the Top End of Northern Australia

Abstract

Use of erythropoiesis-stimulating agents (ESAs) has improved the management of anemia in patients on maintenance hemodialysis (MHD). Iron deficiency and inflammation cause ESAs resistance and are both common among indigenous people of Northern Australia. As part of quality assurance in our Renal Anaemia Management program, we observed that there was use of higher doses of ESAs and adjuvant iron therapy in our MHD patients. This study aimed to explore the relationship among iron studies, inflammation, ESA responsiveness, and ESAs and iron requirements in indigenous patients on MHD from the Top End of Northern Australia. We performed a retrospective cohort analysis of anemia management in a cohort of our patients on MHD. We extracted data for 178 indigenous and 19 non-indigenous patients from 1 March 2009 to 28 February 2010 from the Renal Anaemia Management database, which collects data prospectively in MHD patients. Ninety-nine percent of the whole sample had a ferritin level above the international guidelines threshold of >500 µg/L. Indigenous patients had higher ferritin (1534 ± 245.5 µg/L vs. 1013 ± 323.3 µg/L, P = 0.002). C-reactive protein (CRP) was high in 56.9% of the total cohort. One hundred percent of those with normal CRP had high ferritin (>500 µg/L). C-reactive protein was higher in indigenous than in non-indigenous patients. Erythropoiesis-stimulating agents hyporesponsiveness was higher in indigenous patients (P < 0.0001). There was no significant difference in ESAs hyporesponsiveness among different levels of CRP (P = 0.116), ferritin (P = 0.408), and transferrin saturation (P = 0.503). Indigenous patients required higher total iron dose (2820.30 [2000-4350] vs. 2336.12 [1912-2900], P = 0.02). There was no significant relationship between the high ferritin and CRP. In indigenous dialysis patients, iron therapy and ESAs use are higher. The high iron use is due to a lack of published evidence to guide the administration of iron in patients with high ferritin. The high ferritin and ESAs resistance could not be fully explained by inflammation and need further evaluation. Further studies are required to determine the safe use of iron and management of ESAs resistance in our hemodialysis population.

Hepcidin-25, Mean Corpuscular Volume, and Ferritin as Predictors of Response to Oral Iron Supplementation in Hemodialysis Patients

“…In contrast, HD patients with normal levels of serum hepcidin-25 and ferritin failed to respond to OIT in our study, suggesting that iron absorption and efflux may be inhibited, thereby reducing iron availability for erythropoiesis in HD patients with normal levels of serum hepcidin-25 and ferritin [ 31 ]. This finding has been supported by the following observations: (1) high levels of serum hepcidin-25 and ferritin have been associated with nonresponsiveness to OIT in non-HD patients [ 21 ]; (2) HD patients with high levels of serum ferritin have been resistant to iron supplementation and thus required high dose of iron [ 37 , 38 ]; and (3) HD patients with normal MCV have failed to respond to intravenous iron supplementation [ 32 ].…”

“…In support of our finding, previous studies have shown the predictive value of low serum hepcidin-25 for the good response to intravenous iron supplementation in CKD patients not on dialysis [ 22 ]. In addition, HD patients with high levels of serum ferritin [ 37 , 38 ] and non-HD patients with high levels of serum hepcidin-25 [ 21 ] have been resistant to intravenous or oral iron supplementation. In contrast, other reports showed that serum hepcidin-25 was of minimal value in predicting response to intravenous iron supplementation in HD patients [ 13 ].…”

“…Inflammation could enhance resistance to iron supplementation in HD patients [ 38 , 41 ] because it increases hepcidin-25 and ferritin [ 7 , 9 , 10 ]. In fact, serum levels of hepcidin-25 have been shown to be positively correlated with CRP levels in patients with CKD [ 22 ] and those with HD [ 16 , 28 ].…”

Serum Hepcidin Predicts Uremic Accelerated Atherosclerosis in Chronic Hemodialysis Patients with Diabetic Nephropathy

“…[ 2 ] Despite the widespread use of ESA, near 50% ESRD patients do not reach the target hemoglobin (Hb) levels. [ 3 ] Iron deficiency[ 4 ] and imflammation[ 5 ] are the most common reasons for hyporesponsiveness to ESA therapy in ESRD patients. Serum iron, transferrin saturation (TSAT), the ratio of serum iron to total iron-binding capacity (TIBC), multiplied by 100, and serum ferritin levels are commonly used to evaluate iron status.…”

Plasma oxalate levels in prevalent hemodialysis patients and potential implications for ascorbic acid supplementation

“…We looked at ferritin levels over 3 distinct ranges. The thresholds of 1124 pmol/L and 2472 pmol/L are clinically relevant due to association with ESA resistance [36,37] and may be used in the future to identify patients who may benefit from AA supplementation. Regression analysis revealed that in patients with a pre-HD P[AA] ≤ 100 μM, ferritin levels ≥ 1124 pmol/L or ≥2472 pmol/L were not associated with pre-HD P[Ox] reaching 30 μM.…”