PHARMACOLOGY AND THERAPEUTICS: Edited by Sankar D. Navaneethan
’After a time, the healthy color of the countenance fades’ - Dr Richard Bright describing anaemia of kidney disease 1827 .
Anaemia is the most common haematologic disorder that affects 1.62 billion people worldwide resulting in reduced oxygen delivery to the tissues and organs leading to fatigue, shortness of breath and cognitive impairment . Although iron deficiency is the most common cause, anaemia related to chronic kidney disease (CKD) is well known and is twice as prevalent in CKD population compared with the general population [3,4]. The cause is often multifactorial due to decreased production of erythropoietin (EPO), iron deficiency, shortened red blood cell (RBC) survival, inflammation and accumulation of uremic toxins. In CKD, anaemia has been associated with diminished quality of life, increased cardiovascular events and mortality, and potentially hasten the progression of kidney disease [5,6].
Current standard of care for anaemia in CKD (both in nondialysis-dependent and dialysis-dependent CKD) includes the use of oral or intravenous iron supplementation and erythropoiesis-stimulating agents (ESAs). Management often begins with evaluating patients for correctable causes of anaemia. If iron deficiency is identified with a transferrin saturation less than 30% and ferritin less than 500 ng/ml, current Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends repletion with oral or intravenous iron therapy . If all reversible causes have been addressed and the haemoglobin concentration remains below 10 g/dl, ESA therapy can be initiated. Treatment with ESA reduces transfusion requirements and may improve quality of life, but their effects of cardiovascular events and mortality have not been established . Further, safety concerns have been raised particularly when the haemoglobin concentration increases greater than 11.5 g/dl. ESAs have been associated with hypertension, increased oncologic risk, cardiovascular and thromboembolic risk. In addition, about 10% of ESA users will develop ESA-resistant anaemia  and is associated with a higher mortality risk . Therefore, there have been significant interest in identifying novel agents that has better efficacy and safety profile to manage anaemia among CKD population. In this issue of the Current Opinion in Nephrology and Hypertension, newer pathways and agents being tested in clinical trials have been discussed in detail by experts in the field.
Biologic drugs such as ESAs are often expensive and complicated to produce. Gupta and Wish  reviewed the possible role of using nonbiologic drugs such as EPO mimetic proteins (EMPs) and biologic drugs, EPO fusion proteins to treat anaemia in CKD. EPO mimetic peptides (EMPs) are nonbiologic group of synthetic cyclic peptides that activate the EPO receptor. Unfortunately, the first EMP- Peginesatide was withdrawn from the market due to severe hypersensitivity reaction and safety of EMPs remain unsettled. EPO fusion proteins fuse the N-terminal of recombinant human EPO (rHuEPO) to a human albumin gene or the Fc part of IgG molecule and fusion of the C-terminal of rHuEPO to the C-terminal peptide of human chorionic gonadotropin beta-subunit. This structure aids in achieving increased half-life; however, manufacturing of fusion proteins is complex and will less likely to offer cost savings over current ESAs. In addition, a similar duration of action has been achieved with other biologic ESAs making EPO fusion proteins less desirable.
The role of small molecule inhibitors of prolyl hydroxylase domain enzymes (PHD) inhibitors as a novel therapy in increasing endogenous EPO by stabilizing the cellar hypoxia inducible factor (HIF) is being discussed by Hasegawa et al.  and also by Locatelli and Vecchio Del . HIF stabilization helps improve iron metabolism by suppressing hepcidin levels and promotes iron absorption. Phase 2 clinical trials demonstrated safety and efficacy of these agents in both nondialysis-dependent and dialysis-dependent CKD population and are being tested in larger phase 3 clinical trials . Animal studies have also demonstrated an improvement in metabolic diseases and protection against the development of obesity. The potential downside of PHD inhibitors includes the induction of tumour cell proliferation in hypoxic conditions using HIF signalling. In addition, HIF activation could mediate resistance to chemotherapy and radiation.
The use of recombinant activin type-II receptor (ActRIIA)-IgG-Fc fusion proteins, Sotatercept and Luspatercept, to correct anaemia in patients with CKD is addressed by Wolfgang . Although the mechanisms of action of these agents are poorly understood, it is thought to be related to trapping the ActRIIA ligands that inactivate the transforming growth factor-beta (TGFbeta) family and inhibit erythroid precursors. This leads to an increase in red blood cell production and haemoglobin concentration. Sotatercept has been shown in-vivo studies to inhibit hepcidin transcription in the liver. Experimental studies of Sotatercept reveals efficacy in treating patients with myelodysplastic syndromes, metastatic solid tumours and beta thalassemia. ActRII signalling is a possible target for therapy; however, it is not yet in the public domain and is currently studied in clinical trials. Locatelli and Vecchio Del  discusses the role ESA will play in managing anaemia with the currently available biosimilar agents and future approval of HIF stabilizers. Biosimilar agents are biologic drugs that have a similar mechanism of action; however, they do not offer any clinical advantage over second-generation ESAs. Iron deficiency anaemia is common in CKD and current evidence relating to oral and intravenous iron therapy and ongoing controversies on the subject has been the focus of a review article by Macdougall .
In summary, scientific community has invested significant time and resources to find the ideal agent(s) and appropriate haemoglobin target to improve outcomes for patients with anaemia and CKD for past several decades. We believe that authors of the articles in this issue have elegantly addressed key novel agents that are being investigated and potentially change our clinical practice along with discussing ongoing controversies on the subject.
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Conflicts of interest
S.D.N. has received an investigator-initiated research grant support for Keryx Biopharmaceuticals. Other authors report no conflicts of interest.
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