Combined high serum ferritin and low iron saturation in hemodialysis patients: the role of inflammation

Abstract

Background: Serum ferritin, frequently used as a marker of iron status in individuals with chronic kidney disease, is also an inflammatory marker. The concurrent combination of high serum ferritin and low iron saturation ratio (ISAT) usually poses a diagnostic dilemma. We hypothesized that serum ferritin > or =500 ng/ml, especially in the seemingly paradoxical presence of ISAT level <25%, is more strongly associated with inflammation than with iron in maintenance hemodialysis (MHD) patients.

Design, setting, and participants: In 789 MHD patients in the Los Angeles area, the association of serum ferritin > or =500 ng/ml with inflammatory markers, including IL-6 (IL-6) and C-reactive protein levels, and malnutrition-inflammation score (MIS) was examined.

Results: After multivariate adjustment for case-mix and other measures of malnutrition-inflammation complex, MHD patients with serum ferritin > or =500 ng/ml and ISAT <25% had higher odds ratio for serum C-reactive protein > or =10 mg/L. The area under the receiver operating characteristic curves for the continuum of ISAT and IL-6 in detecting a serum ferritin > or =500 ng/ml were identical (0.57 versus 0.56, P = 0.7). The combination of IL-6 with ISAT yielded a higher area under the receiver operating characteristic curve (0.61) than either ISAT or IL-6 alone (P = 0.03 and P = 0.02, respectively).

Conclusion: In MHD patients, ferritin values above 500 ng/ml, especially in paradoxical conjunction with low ISAT, are associated with inflammation. Strategies to dissociate inflammation from iron metabolism to mitigate the confounding impact of inflammation on iron and to improve iron treatment responsiveness may improve anemia management in chronic kidney disease.

Figure 1.

Scatter plots, regression line, and 95% confidence intervals, reflecting the correlation between serum ferritin and baseline serum transthyretin, iron saturation ratio, total binding capacity, log for C-reactive protein (CRP), log for IL-6 (IL-6), and log for TNF alpha (TNF-alpha).

Figure 2.

Log odds ratio of having ferritin ≥500 ng/ml in 789 maintenance hemodialysis patients. (A) IL-6. (B) Malnutrition-inflammation score (MIS). (C) Iron saturation ratio (%).

Figure 3.

The relationship between the dependent variable, Log odds ratio ferritin ≥500 ng/ml and independent variables (IL-6 and iron saturation ratio).

Figure 4.

Receiver operating characteristic (ROC) curves of probabilities obtained from logistic regression models including (right) iron saturation ratio (ISAT), (middle) IL-6, and (left) ISAT and IL-6 together as independent variables and serum ferritin ≥500 ng/ml as dependent (reference) variable. Values in parentheses are 95% confidence intervals of the calculated area under the ROC curves.

Figure 5.

Log odds ratio of having ferritin ≥500 ng/ml and iron saturation <25% together in 789 maintenance hemodialysis patients. (A) IL-6. (B) Malnutrition-inflammation score (MIS).

Figure 6.

Adjusted odds ratios (ORs) of having IL-6 ≥ 10 (pg/ml) (upper panel) and CRP ≥ 10 (mg/L) (lower panel) according to the four categories of serum ferritin and iron saturation ratio (ISAT) in 789 maintenance hemodialysis patients. Case-mix variables include age, gender, race/ethnicity, diabetes, dialysis vintage, insurance (Medicare), marital status, modified Charlson comorbidity score, dialysis dose (Kt/V), and residual urea clearance (KRU). MICS variables include albumin, log erythropoietin dose, creatinine, hemoglobin, phosphorus, normalized protein catabolic rate (nPCR), bicarbonate, calcium, white blood count (WBC), lymphocyte percent, body mass index (BMI), and log vitamin D dose.