Traditionally, erythropoietin (EPO) deficiency has been known as a central component of the pathophysiology of anemia in chronic kidney disease (CKD). Although renal injury is the primary factor causing EPO deficiency, notably, the efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) highlights that the EPO production potential in residual renal tissue and other sites, such as the liver, remains pharmacologically mobilizable. Nevertheless, in CKD patients, this potential appears unable to be effectively activated by endogenous hypoxia signaling. This phenomenon suggests other factors, such as chronic inflammation, may contribute to the decreased hypoxia sensitivity. As inflammatory cytokines are known to impair erythropoiesis, we reasonably speculate that they also suppress the upstream hypoxic signaling that governs EPO production and play a key role in the blunted endogenous response in CKD. Therefore, this review focuses on how persistent, low-grade chronic inflammation in CKD patients suppresses EPO expression and EPO downstream signaling, disrupts iron metabolism, and impairs hematopoiesis in the bone marrow. Moreover, the gut-kidney axis is an underestimated source of inflammation, with dysfunction resulting from gut flora imbalance, the accumulation of uric toxins, and the activation of inflammatory factors. Herein, we discuss the underlying mechanism of action of chronic inflammation in anemia of CKD, while highlighting that anti-inflammatory therapy is one of the highly effective adjuvant therapies for the future.
Zhang et al. (Thu,) studied this question.