The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease

Background: In the absence of a histological diagnosis, persistent albuminuria is globally accepted as the main diagnostic criteria for diabetic kidney disease (DKD). Methods: In the present retrospective study, we evaluated data from an Italian cohort of 42 deceased diabetic donors (mainly with type 2 diabetes). Using the kidney biopsies obtained at the time of donation to evaluate single or double allocation based on Karpinski score, we determined the prevalence of histological lesions attributable to diabetes. Results: All 42 donors presented with proteinuria in the normal range and an estimated glomerular filtration rate (eGFR) (chronic kidney disease [CKD]-EPI) >60 mL/min/1.73 m2. A kidney biopsy was available for 36 patients; of these, one was not interpretable and 32 showed histopathological lesions consistent with DKD and encompassing all histological classes. Thus, we found a relatively high proportion of histologically proven DKD that had been clinically undiagnosed, as none of the patient had significant proteinuria and eGFR <60 mL/min/1.73 m2. Conclusions: The data we present here support the need to implement routine kidney biopsies in normoalbuminuric diabetic subjects in the early stages of CKD. Such strategy may help to improve risk stratification in diabetic patients and guide therapeutic decisions during the early stages of the disease.

Download Full-text

Nonclinical Characterization of the Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment of Anemia of Chronic Kidney Disease

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.120.265181 ◽

2020 ◽

Vol 374 (2) ◽

pp. 342-353 ◽

Cited By ~ 2

Author(s):

Ughetta del Balzo ◽

Pierre E. Signore ◽

Gail Walkinshaw ◽

Todd W. Seeley ◽

Mitchell C. Brenner ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Novel Treatment ◽

Prolyl Hydroxylase Inhibitor

Download Full-text

Hypoxia-inducible factor-prolyl hydroxylase inhibitor ameliorates myopathy in a mouse model of chronic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00260.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. F1265-F1273 ◽

Cited By ~ 2

Author(s):

Fang-Yuan Qian ◽

Zuo-Lin Li ◽

Yu-Dong Guo ◽

Han-Chao Gao ◽

Li-Hua Gu ◽

...

Keyword(s):

Skeletal Muscle ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Vehicle Group ◽

Acute Ischemia ◽

High Dose ◽

Dependent Manner ◽

Prolyl Hydroxylase Inhibitor

Muscle wasting and diminished physical performance contribute to the morbidity and mortality of chronic kidney disease (CKD), for which no curative therapy exists. Accumulating evidence indicates that impaired angiogenesis occurs in the muscles of CKD models. Therefore, proangiogenesis therapy is considered a potentially effective strategy for limiting CKD-associated myopathy. Hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor (HIF-PHI) stabilizes HIF and enhances muscle angiogenesis during acute ischemia; however, little evidence was available from CKD models. Here, we assessed whether pharmacological activation of HIF by MK-8617 (MK), a novel orally active HIF-PHI, improves CKD-associated myopathy. Mice were divided into sham or CKD groups, and CKD mice were subdivided into CKD + vehicle or MK treatment groups (1.5, 5, or 12.5 mg/kg for 12 wk). In CKD mice, skeletal muscle mass, mitochondrial amount, and exercise capacity decreased compared with sham mice. Compared with the CKD + vehicle group, low (1.5 mg/kg) and medium (5 mg/kg) doses of MK, but not the high dose (12.5 mg/kg), significantly restored these changes and was accompanied by incremental increases in HIF-1α. Furthermore, increased capillary density and area were observed in a MK dose-dependent manner, which is likely related to an improved VEGF response in the skeletal muscle of CKD mice. In addition, macrophage and proinflammatory cytokines, including monocyte chemoattractant protein 1, TNF-α, and IL-6, significantly increased in the high-dose MK group. These results indicate that HIF-PHI provides a potential therapeutic strategy to improve CKD-associated myopathy.

Download Full-text

Vadadustat. Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, Treatment of anemia secondary to chronic kidney disease

Drugs of the Future ◽

10.1358/dof.2016.041.10.2523217 ◽

2016 ◽

Vol 41 (10) ◽

pp. 601

Author(s):

P. Cole

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Prolyl Hydroxylase Inhibitor ◽

Hif Prolyl Hydroxylase ◽

Inhibitor Treatment

Download Full-text

Vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, for treatment of anemia of chronic kidney disease: two randomized Phase 2 trials in Japanese patients

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa060 ◽

2020 ◽

Cited By ~ 2

Author(s):

Masaomi Nangaku ◽

Youssef M K Farag ◽

Emil deGoma ◽

Wenli Luo ◽

Dennis Vargo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Hypoxia Inducible Factor ◽

Japanese Patients ◽

Prolyl Hydroxylase ◽

Fixed Dose ◽

Primary Efficacy ◽

Phase 2 ◽

Prolyl Hydroxylase Inhibitor ◽

Dose Dependent

Abstract Background Vadadustat is an investigational, oral hypoxia-inducible factor prolyl hydroxylase inhibitor in development in Japan for the treatment of chronic kidney disease (CKD)-induced anemia. Methods Two Phase 2, multicenter, double-blind, placebo-controlled studies randomized Japanese patients with nondialysis-dependent (NDD, n = 51) or dialysis-dependent (DD, n = 60) CKD-induced anemia to once-daily vadadustat (150, 300 or 600 mg) or placebo. A 6-week, fixed-dose primary efficacy period was followed by a 10-week vadadustat dose adjustment/maintenance period. The primary endpoint was the mean change in hemoglobin (Hb) level from pretreatment to Week 6. Results Statistically significant (P < 0.01) dose-dependent increases in mean Hb values were observed at Week 6 in all vadadustat groups versus placebo [placebo and vadadustat 150, 300 and 600 mg: −0.47, 0.43, 1.13 and 1.62 (NDD-CKD) and −1.48, −0.28, 0.08 and 0.41 (DD-CKD), respectively]. By Week 16, 91% (NDD-CKD) and 71% (DD-CKD) of vadadustat-treated participants achieved target Hb levels (10.0–12.0 g/dL) and significant dose-dependent changes in iron utilization and mobilization biomarkers were observed with vadadustat. During the primary efficacy period, the incidence of treatment-emergent adverse events (AEs) with placebo and vadadustat 150, 300 and 600 mg was 36, 33, 58 and 54% (NDD-CKD) and 40, 53, 73 and 40% (DD-CKD), respectively. The most common AEs during the primary efficacy period were nausea and hypertension (NDD-CKD) and diarrhea, nasopharyngitis and shunt stenosis (DD-CKD). Of 23 serious AEs in 18 patients, 1 was deemed related (hepatic function abnormal); no deaths were reported. Conclusions The efficacy and safety results from these studies support the development of vadadustat for the treatment of anemia in patients with CKD.

Download Full-text