Roxadustat for Renal Anemia in ESRD from PKD Patients: Is It Safe Enough?

Akizawa et al.¹ report roxadustat’s noninferiority to darbepoetin alfa in treating hemodialysis-dependent CKD anemia in their phase 3 study. However, in this trial, we could not find the exact data of the primary disease of CKD or the proportion that polycystic kidney disease (PKD)^1⇓⇓–4 accounts for. PKD is the fourth leading cause of ESKD in adults worldwide; however, in a phase 2 trial of roxadustat in CKD-associated anemia in Japanese patients, the ratio of polycystic kidney disease was 6.3% (five in 80).²

Roxadustat and other hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors induce hypoxia-like conditions within the cell by stabilizing HIFs and regulating the downstream pathway. Meanwhile, the HIF pathway has been identified as an important novel mechanism of cyst progression through chloride secretion, apoptosis, cell proliferation, cell metabolism, and inflammation in PKD.³ Further, application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype.⁴

Although HIF prolyl hydroxylase inhibitors offer several important advantages, we caution that the long-term use of roxadustat might induce the growth and enlargement of renal cysts in patients with PKD, which can lead to adverse events such as bleeding and infection. Given the data of these trials and hypothesis, the total kidney volume of patients with PKD should be monitored carefully, and these patients deserve long-term follow-up.

Disclosures

All authors have nothing to disclose.

Funding

This work was supported by grants from the Key Research and Development Plan of Zhejiang Province (2019C03028).