Roxadustat for renal patients with hyporesponsiveness to ESAs: a new opportunity?
Ernesto Paoletti1 · Elisabetta Bussalino1,2 · Maura Ravera1
Received: 8 June 2021 / Accepted: 10 June 2021
© Società Italiana di Medicina Interna (SIMI) 2021
Ernesto Paoletti [email protected]
1 Nephrology, Dialysis, and Transplantation, Ospedale Policlinico San Martino, L.go R. Benzi 10, 16132 Genova, Italy
2 University of Genova, Genova, Italy
Introduction:
Anemia still remains a challenge in patients with chronic kidney disease, since it is associated with adverse outcome and great mortality rate [1].
Availability of erythropoiesis stimulating agents (ESA) has profoundly changed this clinical scenario, not only because it has significantly improved the quality of life but also, and especially, the cardiovascular outcome of patients with end-stage kidney disease [2].
Nonetheless, in patients with inflammation, in whom increased hepcidin concentration has been shown to play a key role in affecting iron availability for erythropoiesis, an increase in ESA dose is often needed to achieve target haemoglobin (Hgb) levels, as an effect of poor responsivity to erythropoietic drugs [3]. Unfortunately, this interventional strategy on ESA dosing is reportedly associated with higher risk of major cardiovascular adverse events and mortality [4]. Furthermore, many patients even do not achieve anemia correction after ESAs up-titration.
HIF prolyl hydroxylase (HIF-PH) inhibitors, the novel agents introduced in clinical practice for renal anemia treat- ment, proved to be effective in increasing Hgb levels both in dialysis and non-dialysis CKD patients [5, 6], by stimulating endogenous erythropoietin production. Interestingly, their mechanism of action not only consists of endogenous eryth- ropoietin upregulation, but also of stimulation of transfer- rin, and transferrin receptor gene expression, together with significant reduction of hepcidin, all together allowing better iron disposal [7].
As an effect of this pleiotropic action, HIF-PH inhibitors could be effective in achieving anemia correction in patients who are hyporesponsive to traditional ESA therapy. In this issue of IAEM, Zhou et al. [8] present an interest- ing report on the effectiveness of HIF-PH inhibitors in cor- recting anemia of hemodialysis anemic patients who resulted hyporesponsive to previous ESA therapy. In this study, 32 HD patients with defective response to ESA therapy were fully converted to a Roxadustat-based regimen. Main find- ings of this study are that about one half of patients admin- istered Roxadustat achieved adequate Hgb values, and that inflammatory status, as expressed by persistently increased CRP, was the main factor associated with poor response in the cohort of patient as a whole. Interestingly, the incidence of side effects related to Roxadustat therapy was low, and almost completely improved by symptomatic therapy. These findings are consistent with previous studies that showed a good safety profile for Roxadustat [5, 6]. Even though the study is weakened by the small sample size, the lack of information on hard outcome, and no data on the need of blood transfusion in responder patients as compared to poor responders, however it is of interest since it is the background for considering the new HIF-PH inhibitors as a choice therapy in patients who resulted hyporesponsive to ESA therapy as an effect of a chronic inflammatory status. Although this is not the first study to show the beneficial effect of HIF-PH inhibitors in this setting in hemodialysis patients [9, 10], the paper by Zhou et al. shed further lights on the role of HIF-PH inhibitors in uremic anemia, and claim for systematic adoption of this new class of drugs in renal patients with proven hyporesponsivity to ESAs. Addition- ally, use of Roxadustat for anemia treatment in renal patients with inflammation could reduce the need of IV iron supple- mentation, thus even resulting cost-effective. Furthermore, better disposal of iron could suggest the chance of adopting this new class of anti-anemic medications in CKD patients not on RRT, for whom intravenous iron administration is a hard to deal with task, from a managing point of view.
Further studies, of course, are needed both in uremic dialyzed and not-dialysis CKD patients with proven inflam- matory condition. All these studies should be addressed at confirming both the positive impact of HIF-PH inhibitors in treating anemia of renal disease by a more physiological mechanism of action, and their effectiveness in limiting the occurrence of functional iron depletion.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
Statements on human and animal rights This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent No informed consent.
Reference
1. KDOQI (2006) Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis 47(Suppl 3):S11–S145
2. Mc Causland FR, Claggett B, Burdmann EA, Chertow GM, Cooper ME, Eckardt KU, Ivanovich P, Levey AS, Lewis EF, McGill JB, McMurray JJV, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto RD, Pfeffer MA (2019) Treatment of anemia with darbepoetin prior to dialysis initiation and clinical outcomes: analyses from the trial to reduce cardiovascular events with aranesp therapy (TREAT). Am J Kidney Dis 73:309–315
3. Kalantar-Zadeh K, McAllister CJ, Lehn RS, Lee GH, Nissen- son AR, Kopple JD (2003) Effect of malnutrition-inflammation Internal and Emergency Medicine complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am J Kidney Dis 42:761–773
4. Koulouridis I, Alfayez M, Trikalinos TA, Balk EM, Jaber BL (2013) Dose of erythropoiesis-stimulating agents and adverse outcomes in CKD: a meta-regression analysis. Am J Kidney Dis 61:44–56
5. Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, Tao Y, Liang X, Liu Z, Xing C, Chen J, Luo L, Zuo L, Liao Y, Liu BC, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP (2019) Roxadustat for anemia in patients with kidney disease not receiving dialysis. N Engl J Med 381:1001–1010
6. Chen N, Hao C, Liu BC, Lin H, Wang C, Xing C, Liang X, Jiang G, Liu Z, Li X, Zuo L, Luo L, Wang J, Zhao MH, Liu Z, Cai GY, Hao L, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP (2019) Roxadustat treatment for anemia in patients undergoing long-term dialysis. N Engl J Med 381:1011–1022
7. Maxwell PH, Eckardt KU (2016) HIF prolyl hydroxylase inhibi- tors for the treatment of renal anaemia and beyond. Nat Rev Neph- rol 12:157–168
8. Zhou Y, Chen XX, Zhang YF, Lou JZ, Yuan HB (2021) Roxadus- tat for dialysis patients with erythropoietin hypo-responsiveness: a single-center, prospective investigation. Intern Emerg Med. https://doi.org/10.1007/s11739-021-02738-4
9. Cizman B, Sykes AP, Paul G, Zeig S, Cobitz AR (2018) an explor- atory study of daprodustat in erythropoietin-hyporesponsive sub- jects. Kidney Int Rep 3:841–850
10. Akizawa T, Ueno M, Shiga T, Reusch M (2020) Oral roxadustat three times weekly in ESA-naïve and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: results from two phase 3 studies. Ther Apher Dial 24(6):628–641
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.