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

Abstract

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 longterm follow-up.

Clinical Pharmacokinetics and Pharmacodynamics of Roxadustat

“…This contrasts to the response to the exogenous ESAs with supraphysiological dosing and high EPO concentrations [ 40 ]. More effectively than exogenous ESAs, the HIF stabilizers also improve iron status and transferrin saturation by inhibition of hepcidin, thus leading to increased intestinal iron absorption and better utilization of iron stores in the body [ 43 ]. In contrast to short-term studies [ 7 ], long-term treatment with roxadustat also shows that an iron supplement should be administered [ 10 ].…”

“…Compared with exogenous ESA, roxadustat was associated with more frequent adverse events such as vomiting (RR 1.30, 95% CI 1.02–1.65), headache (RR 1.27, 95% CI 1.05–1.53), and thrombosis (RR 1.31, 95% CI 1.05–1.63) [ 10 ]. Roxadustat might unfavorably lead to the growth of renal cysts in autosomal dominant polycystic kidney disease (ADPKD) because the HIF pathway appears to be involved in cyst progression [ 43 ]. Roxadustat led to reduced thyroid-stimulating hormone levels in a multimorbid hemodialysis patient, but, to date, mechanism and clinical implications are unclear [ 33 ].…”

Risk of infection in roxadustat treatment for anemia in patients with chronic kidney disease: A systematic review with meta-analysis and trial sequential analysis

“…Eleftheriadis et al (2021) supposed that roxadustat might affect the adaptive immune system and increase urinary tract infection and pneumonia incidence. While Liu et al (2021) indicated that long-term use of roxadustat may lead to the progression of renal cysts and cause adverse events of infection. More studies are needed to confirm that roxadustat predisposes patients to infection or that these results are merely statistical differences.…”

Roxadustat: Not just for anemia

“…However, there is some evidence that roxadustat can cause a variety of side effects, mainly diarrhea, vomiting, peripheral edema, headache, back pain, fatigue, and hyperkalemia ( Akizawa et al, 2020c ; Liu et al, 2020 ). In addition, HIF functions in the progression of polycystic kidney disease (PKD), and roxadustat may promote the growth of renal cysts ( Liu et al, 2021 ). A case report found that roxadustat reduced the TSH levels in hemodialysis patients, but the mechanism and clinical significance of this effect is unclear ( Tokuyama et al, 2021 ).…”