ESPN 51th Annual Meeting

ESPN 2018


 
Interleukin-6 and anemia in juvenile mice and children with CKD
Kelly Meza 1 Edwin Patino 1 Vidhi Dalal 1 Divya Bhatia 1 Angara Sureshbabu 1 Perelstein Eduardo 1 Juhi Kumar 1 Stefano Rivella 2 Mary Choi 1 Oleh Akchurin 1

1- Weill Cornell Medical College, New York, NY, USA
2- CHOP, Philadelphia, PA, USA
 
Introduction:

Anemia is a common complication of CKD in children, associated with increased morbidity and poor quality of life. The role of inflammation in the pathogenesis of pediatric renal anemia is incompletely understood.

Material and methods:

Animal model: CKD was induced by 8 weeks of a 0.2% adenine diet, started at 3 weeks of age in wild type (WT) and Il6 knockout (KO) mice. CKD(+) mice were compared with their CKD(-) littermate controls using ANOVA.

Human data: single-center cohort of children with stages 2-5 CKD. Cytokines were measured by a multiplex assay (Meso Scale Discovery). Hepcidin was measured by ELISA (BioIron). Multiple linear regression was used to examine the association between IL-6 and anemia.

Results:

Sixty-three children were enrolled, mean age 12.10±5.8, 60.3% males, 25% with glomerular CKD etiology, mean GFR 44.1±20.4 mL/min/1.73 m2; 38% on iron therapy. Mean hemoglobin (Hgb) was 12.2±1.73 g/dL, and median hepcidin 42.8 (IQR 24.0, 72.1) ng/mL. Screening of 10 cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-α and IFN-γ) showed that only IL-6 was significantly associated with Hgb when adjusted for GFR.

WT and Il6-KO CKD(+) mice had similar renal histology, BUN, and creatinine. WT and Il6-KO CKD(+) mice were anemic, however Il6-KO group had significantly higher Hgb, hematocrit, RBC, MCV, and MCH. WT CKD(+), but not Il6-KO CKD(+) mice exhibited reticulocytosis. Serum iron was higher, and hepcidin lower in Il6-KO than in WT CKD(+) mice.

In children with CKD, IL-6 was inversely associated with GFR (p<0.001), Hgb (p=0.002), hematocrit (p=0.003), RBC (p<0.001), and positively correlated with hepcidin (p=0.02). Stepwise adjustment for covariates demonstrated that the association between IL-6 and Hgb was independent of age, sex, ethnicity, CKD etiology, CKD stage, iron therapy, and hepcidin.

Conclusions:

Deletion of Il6 improved anemia in juvenile mice with CKD, and serum IL-6 was associated with anemia in children with CKD. Upregulation of hepcidin by IL-6 likely plays a role in the pathogenesis of anemia in pediatric CKD. Furthermore, IL-6 may contribute to the development of anemia in CKD independently of hepcidin.