Association of malnutrition-inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients

Abstract

Background: Protein-energy wasting, inflammation and refractory anemia are common in long-term hemodialysis patients. A decreased responsiveness to erythropoiesis-stimulating agents (ESA) is often the cause of the refractory anemia. We hypothesized that the malnutrition-inflammation complex is an independent predictor of decreased responsiveness to ESAs in hemodialysis patients.

Methods: This cohort study of 754 hemodialysis patients was examined for an association between inflammatory and nutritional markers, including the malnutrition-inflammation score (MIS) and responsiveness to ESA. Cubic spline models were fitted to verify found associations.

Results: The mean (±SD) age of patients was 54 ± 15 years, 53% were diabetic and 32% blacks. MIS was worse in the highest quartile of ESAs responsiveness index (ERI, ESA dose divided by hemoglobin) when compared with 1st quartile (6.5 ± 4.5 versus 4.4 ± 3.4; P < 0.001). Both C-reactive protein (log CRP) (β = 0.19) and interleukin-6 (log IL-6) (β = 0.32) were strong and independent predictors of ERI using multivariate linear regression. Serum albumin (β = -0.30) and prealbumin levels (β = -0.14) were inversely associated with ERI. Each 1 SD higher MIS, higher CRP and lower albumin were associated with 86, 44 and 97% higher likelihood of having highest versus three lowest ERI quartiles in fully adjusted models [odds ratio (and 95% confidence interval) of 1.86 (1.31-2.85), 1.44 (1.08-1.92) and 1.97 (1.41-2.78)], respectively. Cubic splines confirmed the continuous and incremental nature of these associations.

Conclusions: Malnutrition-inflammation complex is an incremental predictor of poor responsiveness to ESAs in hemodialysis patients. Further studies are needed to assess whether modulating inflammatory or nutritional processes can improve anemia management.

Keywords: erythropoietin-stimulating agent (ESA) therapy; hemoglobin; inflammatory marker; malnutrition–inflammation complex; responsiveness to ESAs.

FIGURE 1:

Scatter diagram showing the association between two inflammatory markers and ERI in 754 long-term hemodialysis patients. Upper panel: logarithm of CRP; and lower panel: logarithm of IL-6.

FIGURE 2:

Likelihood of the worst ESA hyporesponsiveness using cubic spline analyses to compare the highest (worse) versus three lowest quartiles (as reference) of responsiveness to ESA. Note: adjusted for case-mix (age, gender, race, diabetes mellitus), dialysis center, insurance (Medicaid versus others), Kt/V (single pool), blood hemoglobin, serum iron saturation ratio, the Charlson comorbidity score, dialysis vintage and intact parathyroid hormone.