In Mixed Lymphocyte Reaction, the Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat Suppresses Cellular and Humoral Alloimmunity

Eleftheriadis, Theodoros; Pissas, Georgios; Mavropoulos, Αthanasios; Nikolaou, Evdokia; Filippidis, Georgios; Liakopoulos, Vassilios; Stefanidis, Ioannis

doi:10.1007/s00005-020-00596-0

Cited by 8 publications

(8 citation statements)

References 59 publications

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“…However, we would like to emphasize that it is complex to translate findings from in vitro experiments studying the consequences of HIF stabilization to clinical observations. In the findings cited by Eleftheriadis et al, 3 human PBMCs were exposed to various concentrations (1, 5, 10, or 15 mg/ml) of roxadustat for 7 days, resulting in continuous HIF stabilization, with the 5 and 10 mg/ml concentrations being similar to the maximum plasma concentrations reported among patients who received 1.0 or 2.0 mg/kg of roxadustat. 4 In the OLYMPUS study, 2 roxadustat was administered three times weekly, at least 2 days apart, at a starting dose of 70 mg (maximum dose was capped at the lower of 3.0 mg/kg or 300 mg) for up to 4 years.…”

Section: Authors' Replymentioning

confidence: 63%

Authors’ Reply

Fishbane

El-Shahawy

Van

et al. 2021

JASN

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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-2a and HIF-1a, 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-1a upregulation. Upon T-cell activation, HIF-1a 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-1a and HIF-2a 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. DISCLOSURESV. 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.

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Section: Authors' Replymentioning

confidence: 63%

Authors’ Reply

Fishbane

El-Shahawy

Van

et al. 2021

JASN

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“…6 Furthermore, recent research has demonstrated the other roles of roxadustat, which include suppression of humoral immunity, cell proliferation and inhibition of the differentiation of CD4þ T cells into type 1 helper T and type 17 helper T cell subsets. 22 These other actions might explain why this current case achieved the desired outcome without using steroidbased immunosuppressive agents. This current case was different to another patient that received roxadustat after using immunosuppressant agents.…”

Section: Discussionmentioning

confidence: 85%

Successful application of roxadustat in the treatment of patients with anti-erythropoietin antibody-mediated renal anaemia: a case report and literature review

et al. 2021

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Recombinant human erythropoietin (rHuEPO) has been used worldwide for treatment of renal anaemia due to its good curative effect. However, rHuEPO treatment is associated with a rare but severe complication because of the development of anti-EPO antibodies, which are difficult to treat. Currently, the main treatments for the anti-EPO antibodies include withdrawing the rHuEPO, providing blood transfusions and administrating steroid-based immunosuppressive agents. Although the above methods can alleviate anti-EPO-related anaemia, there are obvious side-effects such as decreased immunity and an increased risk of infection. Therefore, accurately identifying anti-EPO-related anaemia and effectively treating this complication is worth exploring. This current case report describes a 49-year-old female patient with chronic kidney disease that received rHuEPO subcutaneously and then developed anti-EPO antibody-mediated renal anaemia with her haemoglobin levels dropping to 37 g/l. The patient refused to be treated with steroids, so she received 120 mg roxadustat administered orally every 72 h and her Hb level increased to 110 g/l over a few months. This current case report demonstrates that roxadustat can be used to successfully treat anti-EPO antibody-mediated renal anaemia without the use of steroid-based immunosuppressants.

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“…The benefits of HIF-1α stabilizer on inflammatory bowel disease (IBD) also still need further studies (NCT04556383). In addition, roxadustat increases the incidence of infections [ 13 , 17 ], potentially mediates cellular immunity, and inhibits humoral immunity [ 36 , 37 ]. Finally, rhabdomyolysis was also observed three weeks after roxadustat treatment and re-administration in dialysis CKD patients [ 38 ].…”

Section: Clinical Effects Of Roxadustatmentioning

confidence: 99%

Roxadustat: do we know all the answers?

Xiong

Yao

et al. 2023

Biomol Biomed

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Anemia is a common complication of chronic kidney disease (CKD), and its prevalence rises as the disease progresses. Intravenous or subcutaneous erythropoiesis-stimulating agents (ESAs) are advised to treat CKD-associated anemia, since shortage of erythropoietin (EPO) and iron are the main cause of anemia. However, ESA resistance and safety have spurred a lot of interest in the development of alternate anemia therapies. Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that increases erythropoiesis and may modulate iron metabolism, was recently licensed in China, Chile, South Korea, Japan and the European Union for the treatment of CKD-related anemia. Despite this, clinical trials have shown a number of adverse effects, including cardiovascular disease, hyperkalemia, and infections. In addition, of concern is roxadustat's possible effects on other organs and systems. In this review, based on clinical evidence, we discuss the potentially detrimental effects of roxadustat to the known biology on systems other than kidney, and the need for long-term follow-up in order for roxadustat to be approved in more countries in the future.

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In Mixed Lymphocyte Reaction, the Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat Suppresses Cellular and Humoral Alloimmunity

Cited by 8 publications

References 59 publications

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Successful application of roxadustat in the treatment of patients with anti-erythropoietin antibody-mediated renal anaemia: a case report and literature review

Roxadustat: do we know all the answers?

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