Experimental modulation of Interleukin 1 shows its key role in chronic kidney disease progression and anemia

Abstract

Inflammation in chronic kidney disease (CKD) is mostly due to activation of the innate immune system, in which Interleukin-1 (IL-1) is a key player. Anemia of CKD may also be due to erythropoietin (EPO) resistance, clinically associated with inflammation. IL-1 receptor antagonist knockout (RaKO) mice show arthritis and excessive inflammation. Inhibition of IL-1 was shown to be beneficial in many inflammatory conditions, but its role in CKD and anemia is unknown. Here, we report that enhanced inflammation in RaKO mice with CKD provoked both higher degrees of renal insufficiency and anemia in comparison to wild-type CKD, in association with a downregulation of renal hypoxia inducible factor-2 (HIF2) as well as decreased bone marrow EPO-receptor (EPOR) and transferrin receptor (TFR). In contrast, administration of P2D7KK, an anti-IL1b monoclonal antibody, to CKD mice results in a lower grade of systemic inflammation, better renal function and blunted anemia. The latter was associated with upregulation of renal HIF-2α, bone marrow EPO-R and TFR. Altogether, this supports the key role of inflammation, and IL-1 particularly, in CKD progression and anemia. Novel treatments to reduce inflammation through this and other pathways, may improve renal function, attenuate the anemic state or increase the response to exogenous EPO.

Association between periodontitis and chronic kidney disease

“…Systemic uremia affects the immune system by several mechanisms including (a) abnormal neutrophil activity, [42][43][44] (b) increased oxidative stress, 45 and (c) impaired development and maturation of immune cells, 42 dysregulated cytokine release, [46][47][48] and defective barrier immunity. 49,50 This contributes to what has been described as "maladaptive, uncontrolled and persistent" inflammation in patients living with chronic kidney disease, 51 who have been described as simultaneously immunosuppressed (with infectious diseases being a key cause of morbidity and mortality) and systemically inflamed (which may contribute to chronic cardiovascular risk).…”

“…Host immunity plays a crucial role in the development of periodontal breakdown, 41,42 and abnormal immune system function may underlie a number of the familial associations of the disease. Systemic uremia affects the immune system by several mechanisms including (a) abnormal neutrophil activity, 42‐44 (b) increased oxidative stress, 45 and (c) impaired development and maturation of immune cells, 42 dysregulated cytokine release, 46‐48 and defective barrier immunity 49,50 51 who have been described as simultaneously immunosuppressed (with infectious diseases being a key cause of morbidity and mortality) and systemically inflamed (which may contribute to chronic cardiovascular risk) 52 …”

Biological Role, Mechanism of Action and the Importance of Interleukins in Kidney Diseases

“…Renal deterioration was also found based on symptoms such as fibrosis, tubular atrophy dilatation, tissue damage and macrophage infiltration. Interleukin IL-1 itself plays an important role in acute and chronic inflammation, host defense and acute-phase responses, enhancing the infiltration of inflammatory cells and increasing the expression of adhesion molecules [ 210 ].…”

“…Both interleukins and their higher levels are common to each of the types of nephropathy discussed in this review. IL-6 is involved in the development of IgAN, FSMG, DN and CKD, while IL-18 is more frequently studied in LN, DN and AKI [ 192 , 196 , 197 , 198 , 207 , 210 , 228 , 235 , 242 , 244 ]. On this basis, it can be hypothesized that both interleukins could be additional biomarkers facilitating differentiation into the selected type of nephropathy.…”

“…In contrast to proinflammatory interleukins are anti-inflammatory interleukins. The most frequently mentioned in scientific studies on nephropathy was IL-10, occurring, inter alia, in DN, FSMGS, MN, AKI and IL-20 found in CKD and AKI [ 209 , 210 , 215 , 216 , 217 , 218 , 233 , 234 ]. This may lead to the hypothesis that, at the stage of development of individual nephropathies, we are dealing with a higher level of IL-10, while, in the case of acute or chronic inflammation of the kidneys, which may develop as a result of primary diseases, we have more studies confirming the presence of IL-20.…”