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Guidelines 4.1 & 4.2 – Treatment of Anaemia – HIF-PHI Agents

Guidelines 4.1 & 4.2 – Treatment of Anaemia – HIF-PHI Agents

We recommend that treatment with HIF-PHI agents should be offered after iron repletion, to people with symptomatic anaemia (Hb <105 g/L) of CKD (stages 3-5 (eGFR <60 ml/min/1.73m2)) who are not receiving dialysis at the start of therapy and who are likely to benefit in terms of quality of life and physical function and to avoid blood transfusion; especially in people considered suitable for transplantation. (1B)

Guideline 4.1.1 – Treatment of Anaemia – DD-CKD and HIF-PHI Agents

We suggest that that treatment with HIF-PHI agents should be considered after iron repletion, to people with DD-CKD and symptomatic anaemia (Hb <105 g/L) who are likely to benefit in terms of quality of life and physical function and to avoid blood transfusion; especially in people considered suitable for transplantation. (2B)

Guideline 4.1.2 – Treatment of Anaemia – Patients intolerant to ESA

We suggest that that treatment with HIF-PHI agents should be considered as an option, after iron repletion, to people who are intolerant to ESA therapy. (2C)

Guideline 4.1.3 – Choosing between ESA and HIF-PHI therapy for people with non-dialysis dependent CKD and DD-CKD

We suggest, when deciding between ESA and HIF-PHI therapy for people with non-dialysis dependent CKD or DD-CKD, considering the preference of the person with anaemia of CKD, or, where appropriate, their family or carers, the cost of local drug supply, nursing and administration costs and previous treatment with ESA or HIF-PHI. (2B)

Guideline 4.2 – Treatment of Anaemia

We suggest that HIF-PHI administration in HIF-PHI-dependent people should continue during acute illness, surgical procedures or any other cause of hospitalisation, unless there is a clear contraindication such as accelerated hypertension or thrombosis. (2C).

Rationale

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI therapy) also known as HIF stabilisers have emerged as a groundbreaking class of compounds that play a pivotal role in regulating various cellular processes. These oxygen-responsive heterodimeric transcription factors, known as HIFs (hypoxia-inducible factors), are integral to the cellular response to hypoxia, orchestrating a cascade of events that influence vital physiological functions (1). HIFs are particularly noteworthy for their role in managing oxygen homeostasis through their involvement in the production of endogenous erythropoietin (EPO) and iron regulation within the body (1-3).

Under hypoxic conditions, such as those encountered at high altitudes or in cases of anaemia, HIFs activate the transcription of EPO genes within the kidneys and liver, promoting erythropoiesis to enhance oxygen delivery to tissues (1-2). Additionally, HIFs mediate the expression of genes involved in iron transport, uptake, and absorption. These genes contribute to the efficient utilisation of iron, a vital element for multiple physiological processes including oxygen transport, extraction, energy production, and DNA synthesis (1-3).

Erythroferrone (ERFE) is the main erythroid regulator of hepcidin. When erythropoietin is released from the kidney it stimulates the production of new red blood cells and also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and haemoglobin synthesis. The mechanism by which hepcidin is decreased by HIF-PHI therapy has been attributed primarily to increased production of erythroferrone due to increased haematopoiesis (4). Hepcidin is a peptide hormone that modulates the levels of ferroportin – an iron-export channel found on the surface of cells in the duodenum, liver, and macrophages. Hepcidin’s inhibitory action on ferroportin suppresses both intestinal iron absorption and iron release from macrophages, thereby influencing the overall iron balance in the body (5). The connection between HIFs and hepcidin is significant; systemic activation of HIFs prompts an increase in endogenous EPO production and iron utilisation by erythroblasts. This intricate interaction subsequently downregulates hepcidin production in the liver, promoting enhanced intestinal iron absorption and mobilisation from iron stores (6-9). This orchestrated interplay forms a sophisticated regulatory network that maintains iron homeostasis, ensuring optimal functioning of various biological processes.

In the presence of oxygen, prolyl hydroxylase enzymes hydroxylate the oxygen-regulated HIF-α subunit, thereby targeting it for proteasomal degradation (10). HIF-PHI therapy stimulates erythropoiesis primarily by upregulating endogenous EPO production, thereby promoting red blood cell production and ameliorating anaemia. Clinical studies have consistently demonstrated the efficacy and safety of HIF-PHI therapy in addressing the anaemia associated with CKD (11-14).

When there is a reduction of blood oxygen levels, prolyl hydroxylation and degradation of HIF-α subunits are inhibited, resulting in its cellular accumulation and dimerisation with the HIF-β subunits and this heterodimer acts as the transcription factor for the EPO gene (15-16). Prolyl hydroxylation can be pharmacologically inhibited by oral HIF-PHI therapy (17-18), which stimulates erythropoiesis, largely by increasing endogenous EPO production from increased transcription of EPO genes.

Phase three trials have confirmed the efficacy and safety of this class of drug. Currently, Roxadustat and Vadadustat are available and approved in the UK by NICE. Roxadustat should be considered in people with CKD not on dialysis but can be continued when the person progresses to dialysis therapy based on NICE guidance. The drug can be used in people receiving dialysis according to the SmPC but this has not been reviewed by NICE for this purpose (from increased transcription of EPO genes). Vadadustat is recommended, within its marketing authorisation, as an option for treating symptomatic anaemia caused by chronic kidney disease in adults having maintenance dialysis based on NICE guidance.

Health related quality of life in the trials to date have given variable results. Some trials have suggested improvement in Health-related quality of life in comparison to ESA therapy but these are confounded by changes in haemoglobin concentrations (19, 20). Others suggest no significant change in health-related quality of life measures or functional health scores (10-13).

“Potential” clinical and practical benefits of HIF-PHI therapy include:

  • Reduced exposure to high peak serum EPO concentrations
  • Increased endogenous EPO/erythropoietin production
  • Enhanced enteric iron absorption, mobilisation and iron utilisation based on secondary outcome data.
  • Possible reduction in intravenous iron frequency and requirements
  • Oral route of administration

References

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  2. Barrett TD, Palomino HL, Brondstetter TI, et al. Prolyl hydroxylase inhibition corrects functional iron deficiency and inflammation-induced anaemia in rats. Br J Pharmacol 2015; 172: 4078-4088.c
  3. Rankin EB, Biju MP, Liu Q, et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest 2007; 117: 1068-1077.
  4. Nakai T, Iwamura Y, Kato K et al. Drugs activating hypoxia- inducible factors correct erythropoiesis and hepcidin levels via renal EPO induction in mice. Blood Adv 2023; 7 :3793– 805.
  5. CC, Vaja V, Chen S, et al. A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats. Nephrol Dial Transplant 2013; 28: 1733-1743.
  6. Haase VH. Pathophysiological Consequences of HIF Activation: HIF as a modulator of fibrosis. Ann N Y Acad Sci 2009; 1177: 57-65.
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  8. Hanudel MR, Wong S, Jung G, et al. Amelioration of chronic kidney disease-associated anemia by vadadustat in mice is not dependent on erythroferrone. Kidney international 2021; 100: 79-89.
  9. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002; 110: 1037-1044.
  10. Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol 2012; 23: 1631-1634
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  12. Coyne DW, Roger SD, Shin SK, Kim SG, Cadena AA, Moustafa MA, Chan TM, Besarab A, Chou W, Bradley C, Eyassu M, Leong R, Lee TT, Saikali KG, Szczech L, Yu KP. Roxadustat for CKD-related Anemia in Non-dialysis Patients. Kidney Int Rep. 2020 Dec 5;6(3):624-635. doi: 10.1016/j.ekir.2020.11.034.
  13. Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized phase 3 study. J Am Soc Nephrol. 2021;32:737–755.
  14. Shutov E, Sułowicz W, Esposito C, Tataradze A, Andric B, Reusch M, Valluri U, Dimkovic N. Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS). Nephrol Dial Transplant. 2021 Aug 27;36(9):1629-1639. doi: 10.1093/ndt/gfab057
  15. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001; 294: 1337-1340.
  16. Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: A potential new treatment for anemia in patients with CKD. Am J Kidney Dis 2017; 69: 815-826.
  17. Kurata Y, Tanaka T, Nangaku M. Hypoxia-inducible factor prolyl hydroxylase inhibitor in the treatment of anemia in chronic kidney disease. Curr Opin Nephrol Hypertens 2020; 29: 414- 422.
  18. Sugahara M, Tanaka T, Nangaku M. Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anaemia in chronic kidney disease. Kidney international 2017; 92: 306-312.
  19. Johansen, K.L., et al., Effects of Daprodustat on Hemoglobin and Quality of Life in Non- Dialysis CKD Patients: expanded Results of the ASCEND-NHQ Trial. Journal of the American Society of Nephrology, 2022. 33(11): 244.
  20. Csiky, B., et al., Roxadustat for the Maintenance Treatment of Anemia in Patients with End- Stage Kidney Disease on Stable Dialysis: A European Phase 3, Randomized, Open-Label, Active-Controlled Study (PYRENEES). Advances in therapy, 2021. 38(10): 5361-5380