Expert guidance for treating anemia in chronic kidney disease: what is the appropriate drug treatment strategy?

KEYWORDS:

• Anaemia
• chronic kidney disease
• iron deficiency
• erythropoiesis stimulating agents
• HIF-PHD inhibitors
• inflammation

1. Introduction

Anemia is a common complication of chronic kidney disease (CKD) and is associated with poor outcomes. Erythropoietin (EPO) deficiency is the primary cause, but absolute or relative iron deficiency and inflammation often coexist. In this respect, CKD is a significant risk factor for inflammation, cardiovascular disease (CVD), cardiovascular mortality, and impaired quality of life. Anemia is also significantly associated with left ventricular hypertrophy and adverse outcomes [1]; nevertheless, it is often ignored and treated too late after irreversible damage has already developed.

When looking back at the early days of dialysis treatment, iron overload was a significant complication due to the need for frequent transfusions for treating severe anemia, leading to iron chelating treatment with the associated complications. This is a possible explanation for why in the present era of erythropoiesis-stimulating agents (ESAs), there is still therapeutic inertia in using iron supplementation, even if it is crucial to avoid the start of ESA therapy in non-iron repleted patients.

ESA use has revolutionized the management of anemia. These drugs improve quality of life by reducing the symptoms associated with severe anemia, including asthenia. They also reduce the need for blood transfusions, dramatically reducing iron overload, infections, and allo-sensitization.

2. Efficacy and limitations of ESA treatment

The severity of anemia and its response to treatment is highly heterogenous at a given stage of CKD and are often little predictable in the single patient in everyday clinical practice. There is general agreement that ESAs are effective agents and increase Hb levels in a dose-dependent way, even if nearly 5–10% of the patients exhibit resistance or hyporesponse to ESA treatment.

Despite efficacy in many cases, managing anemia in CKD patients is still controversial. Indeed, randomized clinical trials testing ESAs at different hemoglobin (Hb) targets or versus placebo with a rescue therapy found no difference in cardiovascular complications at best or possibly increased morbidity and mortality, especially when aiming at high Hb targets with high ESA doses.

Accordingly, the Kidney Disease Improving Global Outcome (KDIGO) Clinical Practice Guidelines for Anemia in CKD patients [2] suggest a conservative approach with ESA therapy, aiming at a Hb target of <11.5 g/dl. Conversely, the European Renal Best Practice (ERBP) suggests a slightly more permissive Hb target range (10–12 g/dL) with personalized management in between and eventually outside the target range, according to patient characteristics [3]. KDIGO and ERBP strongly recommend that ESAs should not be used to intentionally increase the Hb concentration above 13 g/dL (Table 1) [2,3]. The concept of ‘non-intentionally’ is essential since patients reaching higher Hb levels spontaneously or with low ESA doses are those with the best outcome, possibly because they are less inflamed.

Table 1. Key messages for correcting CKD patient’s anemia.

- Iron supplementation is of paramount importance for correcting anemia in CKD patients
- ESA treatment should be started only after having obtained the correction of iron deficiency
- Targeting near-to-normal Hb levels is dangerous, mainly when using high ESAs doses in hypo-responsive patients
- The Hb target should be individualized by considering patient characteristics and associated risk factors
- ESAs should not be used to intentionally increase the Hb concentration above 13 g/dL
- Avoid too fast anemia correction

3. Novel anemia therapies: hypoxia-inducible factor prolyl hydroxylase inhibitors

In the ensuing years, new evidence, and novel anemia therapies, including hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), have emerged aimed at overcoming the limitations of available ESAS, particularly concerning cardiovascular safety. The drugs were developed following the discovery and understanding of the hypoxia-inducible factor (HIF) pathway and its regulation through the prolyl hydroxylase enzymes (PHD). HIF-PHIs mimic the body’s exposure to hypoxia by inhibiting PHD activity, thus increasing HIF-1α, HIF–2α and HIF-α availability. The final effect is the stimulation of endogenous EPO in the native kidneys and, to a less extent, in the liver.

3.1. Efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors

HIF-PHIs have consistently shown efficacy in anemia correction in patients with anemia of non–dialysis-dependent (NDD) and dialysis-dependent (DD) CKD. In particular, phase-III randomized clinical trials showed non-inferiority when compared to epoetin alfa or darbepoetin alfa or superiority compared to placebo in populations of ESA-treated or ESA-naïve patients [4]. The HIF system is also involved in the regulation of iron homeostasis. Data from phase-II and -III clinical trials consistently showed hepcidin reduction with HIF-PHI [4]; the extent of the stimulated erythropoiesis influences a large part of the effect. Data on iron therapy utilization are less clear as protocols of iron therapy were not standardized in randomized clinical trials. The overall impression is that HIF-PHI allows anemia correction with the possible need for less iron therapy or can contribute to better utilization of iron from existing stores (Table 2).

Table 2. Potential advantages and disadvantages of HIF-HPIs.

Advantages
- Oral administration in ND, peritoneal dialysis, and home hemodialysis (?)
- Improved iron utilization (?) (of importance particularly in ND, peritoneal dialysis, home hemodialysis or dialysis center with limited medical presence)
- Efficacy in inflamed patients (?)
Disadvantages and possible risks
- Less clinical experience compared to ESAs
- Polypharmacy
- Drug-to-drug interaction
- Adherence to oral administration
- Risk of worsening retinopathy
- Risk of cyst growth in autosomal dominant polycystic kidney disease
- Risk of worsening pulmonary hypertension
- Risk of enhancing tumor growth (in common with ESAs)
- Risk of venous or arterial thrombosis (in common with ESAs)

In addition to erythropoiesis and iron metabolism, HIF-PHI may upregulate other hypoxia-sensitive genes involved in several metabolic functions, including vasomotor regulation, angiogenesis, cell growth, cell migration and apoptosis. In CKD patients, the most investigated pleiotropic effect of HIF activation is on cholesterol metabolism. Randomized clinical trials with roxadustat consistently showed a significant decrease in total cholesterol, low-density lipoprotein (LDL) and, to a lesser extent, high-density lipoprotein (HDL) [4]. Similar findings were shown with daprodustat. It should be elucidated if this effect is peculiar to some molecules (roxadustat and daprodustat) or a class effect. The decrease in LDL cholesterol could translate into a clinical advantage in terms of cardiovascular risk reduction more in the earlier stages of CKD, as in dialysis patients, atherosclerotic complications are more due to vascular calcifications rather than cholesterol deposition. Recently, some murine models have shown that the activation of the HIF system could worsen vascular calcifications [5]; high phosphate levels could be a mediator of the effect [6]. Unfortunately, most CKD patients enrolled in the trials were already in stages IV and V of CKD, possibly precluding the possibility of detecting a positive impact on the cardiovascular system.

4. Expert opinion

Despite their limitations, ESAs and iron treatment are still the gold standards for anemia in CKD patients. There is general agreement that HIF-PHIs are effective drugs in correcting anemia and maintaining Hb levels with a completely different mechanism of action than current ESAs. They also differ from ESA since they are administered orally. HIF- PHIs may be particularly useful in hypo-responsive inflamed patients because of the reported better absorption and mobilization of iron stores from macrophages, reducing the need for escalating iron and ESAs doses. It is still an open question whether this is a peculiar characteristic of some HIF-PHIs or a class effect.

At the start of clinical development, great expectation was put on the possibility that HIF-PHI could have better safety on the cardiovascular outcome than ESA. Indeed, they usually expose patients to relatively low EPO plasma concentrations due to the endogenous stimulation of EPO production. This should theoretically translate into lower toxicity for the endothelium with a potentially lower cardiovascular risk.

Overall, phase-III clinical trials did not prove this hypothesis but showed non-inferiority compared to ESAs or placebo. Moreover, some phase-III trials, especially with vadadustat [7] raised safety issues on cardiovascular and thrombotic events in NDD patients. The interpretation of this finding is complicated by several considerations. Surprisingly, the major concerns related to HIF-PHI use are about NDD-CKD patients, who usually have fewer comorbidities, lower dose needs, less severe anemia and less inflammation than dialysis patients. It is well known that inflammation is considered the Achilles’ heel of the efficacy and safety of current ESAS. An alternative explanation could be that the findings occurred by chance due to a relatively low statistical power of the study in NDD-CKD patients, possibly because NDD-CKD patients experience fewer cardiovascular events when current EASs are given at a lower dose in a selected population fulfilling the criteria for enrollment in a randomized clinical trial. Moreover, the PRO2TECT study [7] showed a geographical distribution of the risk of cardiovascular and thrombotic events in patients randomized to vadadustat (surprising higher outside the United States). It is then possible that patient characteristics and practice patterns may also play a role. Of note, a recent meta-analysis of ten randomized clinical trials did not show a higher risk for cardiovascular events or mortality following vadadustat treatment [8]. Nevertheless, in its rejection of vadadustat, the Food and Drug Administration (FDA) cited an increased risk of thromboembolic events driven by vascular access thrombosis in dialysis patients. Of note, among possible mechanisms of enhanced thrombosis, HIF-1α downregulates protein S levels in cultured liver cells following hypoxic exposure [9]. However, in vitro studies often cannot replicate the complex microenvironment of tissue hypoxia.

Overall, HIF-PHIs are well-tolerated drugs in terms of side effects. Given their mechanism of action that possibly involves several pathways other than erythropoiesis, several safety aspects deserve special attention. First, HIF-1a activation could cause the stimulation of vascular endothelial growth factor (VEGF) and possibly be involved in cancer development and growth. This possibility was overseen during phase-II randomized clinical trials, and no significant increases in VEGF levels were found following HIF-PHI treatment. However, no clear evidence on reference values for normality ranges is available in this respect. Regardless, phase-III clinical trials did not show increased cancer risk [4]. The only exception is for the Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Non-Dialysis ASCEND-ND) study [10]. In this randomized clinical trial, daprodustat-treated patients had a significantly higher rate of cancer-related death, tumor progression, or recurrence than darbepoetin alfa. However, absolute numbers were low and post-hoc analyses showed a lower risk, possibly suggesting statistical fluctuation [10].

VEGF increase is also potentially linked to retinal lesions; available data do not support a higher risk of de-novo or deteriorating proliferative retinopathy in diabetic and non-diabetic patients (Table 2) [11]. Caution should also be taken when using HIF-PHI in patients with polycystic kidney disease or pulmonary hypertension (Table 2). According to some case reports, roxadustat, one of the HIF-PHI molecules, could influence thyroid function, causing central hypothyroidism in some patients [12].

Quality of life is among the priorities from the patient perspective. The only published few studies evaluating the quality of life in NDD-CKD did not disclose any significant difference versus placebo [13,14] or darbepoetin alfa [15]. According to a preliminary report of the ASCEND-NHQ study, ND-CKD patients receiving daprodustat improved their vitality score (fatigue) significantly compared to placebo. However, they achieved higher Hb levels. Also, when the quality of life was evaluated in dialysis patients, it did not differ significantly between roxadustat and ESA. Despite that, anemia-related symptoms and physical and mental status are often neglected in clinical trials, which also applies to HIF-PHI.

Besides patients’ well-being, which is not measured explicitly by questionnaires on health-related quality of life, HIF-PHIs are administered orally, avoiding pain and reaction at the injection site as it may occur with subcutaneous ESAs. However, the risk of non–adherence should be considered, particularly in hemodialysis patients.

To conclude, HIF-PHIs are superior to placebo and non-inferior to ESA in correcting anemia. For this reason, they should be considered valid alternatives to current ESAs. To date, none of the HIF-PHIs is found superior to the current ESAs, and none have been approved by the FDA, as both roxadustat and vadadustat were denied because of cardiovascular disease safety. In addition, vadadustat was denied because of concerns of hepatic toxicity. Following the revision of different data sets, the European Medicine Agency (EMA) approved roxadustat for clinical use, recommending avoiding the shift from ESA therapy in the absence of clinical reasons. Daprodustat has not completed yet the approval process of both EMA and FDA.

HIF-PHIs may be more effective in subjects hypo-responsive to ESAs; if confirmed, this may be a clinical situation where these drugs may be preferred to the current ESAs (Table 2). Other positive or negative effects should be expected with more extensive use. For complete confidence from physicians, HIF-PHIs need to be well tolerated and used by a large patient population in everyday clinical practice over a long time, clarifying their potential side effects, including cancer risk and thrombosis (Table 2). However, the accumulating data are progressively reassuring.

Declaration of interest

F. Locatelli has served as an advisory board member for Amgen, Astellas, Baxter, GSK, Otsuka, Travere, Vifor Pharma; and has received speaker fees from Amgen, Astellas and Vifor Pharma. L. Del Vecchio has served as an advisory board member for Astellas, Amgen and Vifor Pharma.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have served on advisory boards for the developers of roxadustat, vadadustat, and daprodustat. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.