therapeutic indications. Aside from undesirable on-target effects, such as increased erythropoietin production and raised red blood cell numbers (also observed by the authors), major issues that will have to be addressed include the need for biomarkers that reliably identify patients who would benefit from treatment with HIF activators, the time point at which treatment would need to be started, the duration of treatment, potential adverse effects associated with long-term treatment, and the efficacy of treatment in patients with advanced disease.While many questions remain unanswered, the studies by Nordquist and colleagues provide strong rationale for targeting O 2 metabolism and renal hypoxia for the prevention and treatment of hyperglycemic renal injury. Their findings will certainly prompt additional investigations into how the PHD/HIF pathway can be further exploited for therapeutic intervention in DN.