On the Increased Event Rate of Urinary Tract Infection and Pneumonia in CKD Patients Treated with Roxadustat for Anemia

Oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors have recently been added to the nephrologist’s armament against renal anemia. Many studies confirmed the efficacy and the relatively safe profile of this new class of drugs. The recently published results from a randomized phase 3 trial about roxadustat for treating anemia in patients with CKD, not on dialysis, confirmed its efficacy and safety. However, in the same study, the event rate of urinary tract infection and pneumonia appeared higher for roxadustat than the placebo group. According to the authors, there is no clear biologic mechanism for this observation.1 Interestingly, randomized phase 3 trials, with a smaller sample size and a shorter duration, for treating anemia in patients on chronic dialysis with roxadustat detected a higher incidence of upper respiratory infection in the roxadustat group than in the epoetin alfa or darbepoetin alfa group.2,3 Oral HIF prolyl hydroxylase inhibitors affect erythropoietin production and iron metabolism by increasing HIF-2α and HIF-1α, respectively. However, HIFs are expressed in any cell type and transcribe too many genes. Experimental data support that roxadustat might increase certain infections by affecting the adaptive immune response through HIF-1α upregulation. Upon T-cell activation, HIF-1α is upregulated even in the absence of anoxia and affects cell metabolism, proliferation, and differentiation toward various effector or regulatory phenotypes.4 In the human mixed-lymphocyte reaction, an established experimental model of alloimmunity, roxadustat increased HIF-1α and HIF-2α levels in CD4+ T cells, decreased their proliferation, and induced apoptosis. In parallel, roxadustat facilitated CD4+ T-cell differentiation toward a T helper 2 (Th2) cell phenotype instead of a Th1 phenotype, and into a regulatory T cell phenotype instead of a Th17 phenotype. Finally, roxadustat suppressed humoral alloimmunity, as assessed by alloantibody production.5 Thus, in our opinion, the increased incidence of certain infections in the patients treated with roxadustat might be the result of its effect on the adaptive immune response. The pleiotropic effects and possible side effects of HIF prolyl hydroxylase inhibitors should be evaluated further. Disclosures V. Liakopoulos reports receiving research funding from Baxter and Genesis, and serving as a member of the World Kidney Day Steering Committee. All remaining authors have nothing to disclose. Funding None.