Similarly, if the hypothesis is borne out that increased cardiovascular morbidity and mortality in normalization of hemoglobin in anemia of CKD results from the use of high doses of ESAs, it is biologically plausible that HIF-PHIs allow the benefits of increased hemoglobin without the risks associated with high-dose ESAs, by normalizing hemoglobin but with much lower peak serum EPO levels compared with high-dose ESA therapy. The gene discussed is EPO; the disease is anemia (phenotype).