ESPN 51th Annual Meeting

ESPN 2018


 
Systemic inflammation exacerbates both renal damage and anemia of chronic kidney disease
DANIEL LANDAU 1 INBAR BANDACH 2 YAEL SEGEV 2

1- Pediatrics Dept B, SCHNEIDER CHILDRENS MEDICAL CENTER OF ISRAEL. Sackler School of Medicine, Tel Aviv University, Israel
2- DEPARTMENT OF MICROBIOLOGY AND IMMUNOLOGY, FACULTY OF HEALTH SCIENCES, BEN GURION UNIVERSITY, Beer Sheva, Israel
 
Introduction:

 Chronic kidney disease (CKD) related anemia is commonly thought to be due to impaired renal erythropoietin (EPO) synthesis, which is controlled by hypoxia inducible factor (HIF). In addition, inflammation of CKD is a known driver of hepcidin-mediated iron malabsorption. However, the exact contribution of different degrees of inflammation in CKD are not well characterized. The aim of this study was to examine the effects of enhanced inflammation on renal damage and anemic status in a mouse model of CKD  by adenine (Ad) diet (0.2%). 

Material and methods:

 IL-1 receptor antagonist (IL1Ra) knockout (RaKO) (which show excessive inflammation) and wild-type (WT) mice were divided into 4 groups: (WT, WT-Ad, RaKO, RaKO-Ad) and sacrificed after 10 weeks. For a control model of anemia (C-A), WT mice were bled every two days for a week.

Results:

 Higher levels of serum creatinine, kidney inflammation (such as IL-6 and p-STAT3) and fibrosis were seen in RaKO-Ad Vs WT-Ad. Arthritis in RaKO mice was associated with increased peripheral WBC count as well as liver CRP, was more accentuated in RaKO-Ad and most visible in the ankle joints. Hematocrit levels were decreased in both Ad groups, but especially in RaKO-Ad. Serum iron and MCV levels were significantly reduced in both Ad group. The response to bleeding induced anemia (CA) included: low liver hepcidin, elevated renal HIF2, increased bone marrow (BM) EPO-R and transferrin receptor (TFR) and was opposite to results in CKD animals. Liver hepcidin mRNA levels were increased in RaKO-Ad. Renal HIF2, BM EPO-R mRNA and  BM TFR mRNA were significantly decreased in both Ad groups, especially in RaKO-Ad. 

Conclusions:

There is a higher degree of renal insufficiency, anemia and arthritis in RaKO-Ad. Anemia of CKD is accentuated by systemic inflammation seen in RaKO-Ad, which leads to both hepcidin mediated iron malabsorption as well as an abnormal response of the HIF-EPO-EPO-R axis. This supports the key role of inflammation in CKD-associated anemia and in the exacerbation of renal damage. Therefore, anti-inflammatory treatments may attenuate the renal damage and improve EPO responsiveness.