Treatment options for renal anemia become more diverse

Dong Ki Kim, Department of Nephrology, SNUH

“HIF-PHIs may be considered for patients with functional iron deficiency or poor ESA response”

Vadanem enters market…”Selecting the right mechanism for each patient is important”

Treatment of anemia associated with chronic kidney disease is moving beyond simply adjusting doses of erythropoiesis-stimulating agents (ESAs) toward selecting an appropriate mechanism based on each patient’s iron metabolism, inflammatory status, and treatment response.

ESAs, which have led the treatment of anemia in dialysis patients for decades, remain the standard of care. More recently, however, oral hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), which stimulate endogenous erythropoietin (EPO) production by harnessing the body’s response to hypoxia, have entered clinical practice in Korea and broadened the range of options.

The use of the new mechanisms is deemed to be useful in patients who struggle to reach their target hemoglobin level despite ESA therapy or who have sufficient iron stores, as measured by ferritin, but cannot effectively use that iron for erythropoiesis.

At a recent interview with Dailypharn, Dong Ki Kim, Professor of Nephrology at Seoul National University Hospital, said, “For the past 30 years, anemia treatment in dialysis patients has essentially revolved around setting the ESA dose and determining when to supplement iron.”

Anemia common among dialysis patients…linked to cardiovascular risk

Dong Ki Kim, Department of Nephrology, SNUH

Anemia is a common complication in dialysis patients. Declining kidney function reduces production of EPO, which stimulates red blood cell production. Uremic toxins, chronic inflammation, impaired iron utilization, repeated blood sampling, and blood loss during dialysis also contribute to the condition.

The burden on patients can also be substantial. As anemia worsens, it may cause not only shortness of breath and fatigue but also a broad decline in quality of life, affecting exercise capacity, concentration, sleep and social activities.

Kim noted that anemia management is closely linked to the long-term prognosis of dialysis patients and goes beyond relieving symptoms.

He said, “Cardiovascular disease is one of the primary causes of death in dialysis patients. When anemia occurs, heart rate and cardiac output increase to compensate for it, which increases the burden on the heart and can raise the risk of cardiovascular complications such as left ventricular hypertrophy.”

“Because anemia is closely associated with outcomes such as hospitalization and death, it should not be viewed simply as an adjunctive treatment aimed at relieving symptoms,” he added.

Excessively raising hemoglobin or correcting it too rapidly must also be avoided. Management within an appropriate range requires a comprehensive assessment of not only the patient’s hemoglobin and iron status but also inflammation, bleeding, cardiovascular disease and ESA responsiveness.

Patients with poor ESA response and iron deficiency…intensify treatment gaps

ESAs have transformed the treatment of renal anemia. By reducing the frequent transfusions previously required and improving anemia and quality of life, they have remained the mainstay of treatment for many years.

However, not every patient responds to ESA therapy.

In patients with chronic inflammation, levels of hepcidin—the hormone that regulates iron metabolism—increase, preventing the body from effectively using iron even when sufficient stores are present. This is commonly seen in patients with diabetes, infections, vascular access problems, peritonitis, chronic wounds, or autoimmune diseases.

Patients with functional iron deficiency, characterized by those who have adequate serum ferritin but low transferrin saturation (TSAT), may also fail to achieve the desired response despite receiving ESAs and iron supplementation.

Kim explained, “In these patients, continually increasing the ESA dose may offer limited efficacy, and the risk of adverse effects must also be considered. This has led to a rising, constant demand for treatment options that control anemia through mechanisms other than ESAs.”

HIF-PHIs are one new option that may help address these limitations. They inhibit the prolyl hydroxylase enzymes responsible for degrading hypoxia-inducible factor, thereby activating the body’s hypoxia-response pathway and stimulating endogenous EPO production. Their effects on pathways involved in iron absorption, transport, and utilization also distinguish them from conventional ESAs.

“While ESAs stimulate red blood cell production by supplying EPO from outside the body, HIF-PHIs use the patient’s own hypoxia-adaptation system. An important distinction is that they affect iron metabolism, including hepcidin, helping mobilize stored iron for erythropoiesis.”

“Who to use HIF-PHIs”…specifying subject patients

In Korea, the oral HIF-PHI Vadanem (vadadustat) is used to treat anemia associated with chronic kidney disease in adults receiving dialysis. It is available in 150 mg and 300 mg strengths and can be taken orally once daily.

In the global INNO2VATE 1 and 2 trials in dialysis patients, Vadanem demonstrated noninferiority to the conventional ESA darbepoetin alfa in improving hemoglobin levels.

Based on his clinical experience, Kim identified several patient groups in whom HIF-PHI treatment may be considered: patients newly starting dialysis; patients with functional iron deficiency or inflammation who respond poorly to ESAs; and peritoneal dialysis patients for whom injections are burdensome.

“Patients beginning dialysis may retain a relatively greater degree of residual kidney function and, in some cases, have less severe inflammation. For these patients, an HIF-PHI that stimulates endogenous EPO production may be an option.”

He added, “HIF-PHIs may also be considered in patients with functional iron deficiency, whose ferritin is sufficient but whose low TSAT indicates that iron is not being properly mobilized, or in patients whose response to ESAs is impaired by inflammation.”

However, closer management is needed when patients with poor response who had been receiving high-dose ESAs switch to an HIF-PHI. Their previous ESA requirements and changes in hemoglobin levels must be monitored until the appropriate HIF-PHI dose is established.

“In patients switched to an HIF-PHI, I have generally seen hemoglobin remain within the target range or rise gradually during the first 4-8 weeks, rather than changing abruptly. It is important to monitor both hemoglobin and iron-related parameters regularly during treatment.”

Their oral route of administration is another reason HIF-PHIs may be considered in clinical practice.

“What patients mention most often is that they appreciate not having to receive injections. For healthcare professionals, replacing the management of injection schedules and doses with once-daily administration allows greater focus on maintaining the patient’s hemoglobin at a stable level.”

Reimbursement remains a challenge…”Treatment should match the patient”

Kim also pointed to the need for policy improvements. Under the current reimbursement framework, restrictions on combining HIF-PHIs with ESAs make it difficult to use flexible treatment strategies during the transition between therapies.

Kim said, “It is encouraging that reimbursement for the new drug has improved patient access. However, greater flexibility is needed when transitioning between treatments, and the hemoglobin target range may also need to be reconsidered based on individual patient conditions.”

He added that the narrow hemoglobin range recognized for reimbursement during maintenance therapy and the restriction of eligible use to dialysis patients may warrant discussion as further clinical evidence emerges.

He said, “It is disappointing that the hemoglobin range eligible for reimbursement during maintenance therapy is rather narrow. There may be room for adjustment, particularly when compared with the target ranges recommended in international guidelines.”

Kim added, “As Korean real-world clinical data accumulate, more specific criteria for the use of HIF-PHIs may be developed to better reflect the characteristics of Korean dialysis patients.”

He emphasized, “Going forward, treatment decisions will increasingly focus on determining which mechanism of action is most appropriate for each patient and which therapy can maintain stable hemoglobin levels. With more options available, anemia treatment can become more individualized and precise.”