Inhibition of Prolyl Hydroxylases Increases Erythropoietin Production in ESRD

Abstract

The reasons for inadequate production of erythropoietin (EPO) in patients with ESRD are poorly understood. A better understanding of EPO regulation, namely oxygen-dependent hydroxylation of the hypoxia-inducible transcription factor (HIF), may enable targeted pharmacological intervention. Here, we tested the ability of fibrotic kidneys and extrarenal tissues to produce EPO. In this phase 1 study, we used an orally active prolyl-hydroxylase inhibitor, FG-2216, to stabilize HIF independent of oxygen availability in 12 hemodialysis (HD) patients, six of whom were anephric, and in six healthy volunteers. FG-2216 increased plasma EPO levels 30.8-fold in HD patients with kidneys, 14.5-fold in anephric HD patients, and 12.7-fold in healthy volunteers. These data demonstrate that pharmacologic manipulation of the HIF system can stimulate endogenous EPO production. Furthermore, the data indicate that deranged oxygen sensing-not a loss of EPO production capacity-causes renal anemia.

HIF2α signaling inhibits adherens junctional disruption in acute lung injury

“…We observed that the small-molecule PHD2 inhibitor Fg4497, which was used to activate HIF2α signaling, prevented pulmonary edema and significantly improved mortality in experimental models of sepsis-induced ARDS. Since the same PHD inhibitor is being used in early clinical trials to treat anemia in patients with chronic kidney disease (49), this may also be a feasible and novel approach to treat ARDS patients.…”

Physiology of the Renal Interstitium

“…In this regard, differential expression of hypoxia-inducible factor (HIF) proteins, of globin transcription factor proteins, or hypermethylation of regulatory elements has been suggested to be involved (48,50). Relevance of such knowledge lies in possible use of these pathways to rescue endogenous Epo production in anemic patients (51).…”

Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glycoform analysis

“…Patients with end-stage renal disease require life-long therapy with recombinant EPO (rhEPO), but currently, therapeutic approaches for enhancing endogenous non-renal production of EPO is of high interest, as discussed in recent reviews [5,6]. Pharmacological manipulation of the hypoxia-inducible transcription factor (HIF) has been shown to stimulate endogenous EPO production [7]. Methods for up-regulating production of EPO from the liver seem especially attractive as an alternative to therapy with rhEPO when kidney production has ceased [8].…”