Anemia of chronic kidney disease: Treat it, but not too aggressively

Two ESA preparations

The two ESAs that have traditionally been used in the treatment of renal anemia are recombinant human erythropoietin and darbepoietin alfa. They appear to be equivalent in terms of safety and efficacy.⁷⁰ However, darbepoietin alfa has more sialic acid molecules, giving it a higher potency and longer half-life and allowing for less-frequent injections.^71,72

In nondialysis patients, recombinant human erythropoietin is typically given every 1 to 2 weeks, whereas darbepoietin alfa can be given every 2 to 4 weeks. In dialysis patients, recombinant human erythropoietin is typically given 3 times per week with every dialysis treatment, while darbepoietin alfa is given once a week.

Target hemoglobin levels: ≤ 11.5 g/dL

In light of the four trials described in Table 1, the international Kidney Disease: Improving Global Outcomes (KDIGO) guidelines⁶⁰ recommend the following (Table 2):

For patients with chronic kidney disease who are not on dialysis, ESA therapy should not be initiated if the hemoglobin level is higher than 10 g/dL. If the hemoglobin level is lower than 10 g/dL, ESA therapy can be initiated, but the decision needs to be individualized based on the rate of fall of hemoglobin concentration, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy, and the presence of symptoms attributable to anemia.

For patients on dialysis, ESA therapy should be used when the hemoglobin level is between 9 and 10 g/dL to avoid having the hemoglobin fall below 9 g/dL.

In all adult patients, ESAs should not be used to intentionally increase the hemoglobin level above 13 g/dL but rather to maintain levels no higher than 11.5 g/dL. This target is based on the observation that adverse outcomes were associated with ESA use with hemoglobin targets higher than 13 g/dL (Table 1).

Target iron levels

Regarding iron stores, the guidelines recommend the following:

For adult patients with chronic kidney disease who are not on dialysis, iron should be given to keep transferrin saturation above 20% and ferritin above 100 ng/mL. Transferrin saturation should not exceed 30%, and ferritin levels should not exceed 500 ng/mL.

For adult patients on dialysis, iron should be given to maintain transferrin saturation above 30% and ferritin above 200 ng/mL.

The upper limits of ferritin and transferrin saturation are somewhat controversial, as the safety of intentionally maintaining respective levels greater than 30% and 500 ng/mL has been studied in very few patients. Transferrin saturation should in general not exceed 50%.

High ferritin levels are associated with higher death rates, but whether elevation of ferritin levels is a marker of excessive iron administration rather than a nonspecific acute-phase reactant is not clear. The 2006 guidelines⁶⁰ cited upper ferritin limits of 500 to 800 ng/mL. However, the more recent DRIVE trial⁶⁷ showed that patients with ferritin levels of 500 to 1,200 ng/mL will respond to intravenous administration of iron with an increase in their hemoglobin levels. This has led many clinicians to adopt a higher ferritin limit of 1,200 ng/mL.

Hemosiderosis, or excess iron deposition, was a known consequence of frequent transfusions in patients with end-stage renal disease before ESA therapy was available. However, there have been no documented cases of clinical iron overload from iron therapy using current guidelines.⁷³

These algorithms are nuanced, and the benefit of giving intravenous iron should always be weighed against the risks of short-term acute toxicity and infection. Treatment of renal anemia not only requires in-depth knowledge of the topic, but also familiarity with the patient’s specific situation. As such, it is not recommended that clinicians unfamiliar with the treatment of renal anemia manage its treatment.

PARTICULAR CIRCUMSTANCES

Inflammation and ESA resistance

While ESAs are effective in treating anemia in many cases, in many patients the anemia fails to respond. This is of particular importance, since ESA hyporesponsiveness has been found to be a powerful predictor of cardiovascular events and death.⁷⁴ It is unclear, however, whether high doses of ESA are inherently toxic or whether hyporesponsiveness is a marker of adverse outcomes related to comorbidities.

KDIGO defines initial hyporesponsiveness as having no increase in hemoglobin concentration after the first month of appropriate weight-based dosing, and acquired hyporesponsiveness as requiring two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable.⁶⁰ Identifying ESA hyporesponsiveness should lead to an intensive search for potentially correctable factors.

The two major factors accounting for the state of hyporesponsiveness are inflammation and iron deficiency.^75,76

Inflammation. High C-reactive protein levels have been shown to predict resistance to erythropoietin in dialysis patients.⁷⁷ The release of cytokines such as tumor necrosis factor alpha, interleukin 1, and interferon gamma has an inhibitory effect on erythropoiesis.⁷⁸ Additionally, inflammation can alter the response to ESAs by disrupting the metabolism of iron⁷⁹ through the release of hepcidin, as previously discussed.³⁸ These reasons likely account for the observed lower response to ESAs in the setting of acute illness and explain why ESAs are not recommended for correcting acute anemia.⁸⁰

Iron deficiency also can blunt the response to ESAs. Large amounts of iron are needed for effective erythropoietic bursts. As such, iron supplementation is now a recognized treatment of renal anemia.⁸¹

Other factors associated with hyporesponsiveness include chronic occult blood loss, aluminum toxicity, cobalamin or folate deficiencies, testosterone deficiency, inadequate dialysis, hyperparathyroidism, and superimposed primary bone marrow disease,^82,83 and these should be addressed in patients whose anemia does not respond as expected to ESA therapy. A summary of the main causes of ESA hyporesponsiveness, their reversibility, and recommended treatments is presented in Table 3.

Antibody-mediated pure red-cell aplasia. Rarely, patients receiving ESA therapy develop antibodies that neutralize both the ESA and endogenous erythropoietin. The resulting syndrome, called antibody-mediated pure red-cell aplasia, is characterized by the sudden development of severe transfusion-dependent anemia. This has historically been connected to epoetin beta, a formulation not in use in the United States. However, cases have been documented with epoetin alfa and darbepoetin. The incidence rate is low with subcutaneous ESA use, estimated at 0.5 cases per 10,000 patient-years⁸⁴ and anecdotal with intravenous ESA.⁸⁵ The definitive diagnosis requires demonstration of neutralizing antibodies against erythropoietin. Parvovirus infection should be excluded as an alternative cause of pure red­cell aplasia.

ANEMIA IN CANCER PATIENTS

ESAs are effective in raising hemoglobin levels and reducing transfusion requirements in patients with chemotherapy-induced anemia.⁸⁶ However, there are data linking the use of ESAs to shortened survival in patients who have a variety of solid tumors.⁸⁷

Several mechanisms have been proposed to explain this rapid disease progression, most notably acceleration in tumor growth^88–90 by stimulation of erythropoietin receptors on the surface of the tumor cells, leading to increased tumor angiogenesis.^91,92

For these reasons, treatment of renal anemia in the setting of active malignancy should be referred to an oncologist.

NOVEL TREATMENTS

Several new agents for treating renal anemia are currently under review.

Continuous erythropoiesis receptor activator

Continuous erythropoiesis receptor activator is a pegylated form of recombinant human erythropoietin that has the ability to repeatedly activate the erythropoietin receptor. It appears to be similar to the other forms of erythropoietin in terms of safety and efficacy in both end-stage renal disease⁹³ and chronic kidney disease.⁹⁴ It has the advantage of an extended serum half-life, which allows for longer dosing intervals, ie, every 2 weeks. Its use is currently gaining popularity in the dialysis community.

HIF stabilizers

Our growing understanding of the physiology of erythropoietin offers new potential treatment targets. As previously described, production of erythropoietin is stimulated by HIFs. In order to be degraded, these HIFs are hydroxylated at their proline residues by a prolyl hydroxylase. A new category of drugs called prolyl-hydroxylase inhibitors (PDIs) offers the advantage of stabilizing the HIFs, leading to an increase in erythropoietin production.

In phase 1 and 2 clinical trials, these agents have been shown to increase hemoglobin in both end-stage renal disease and chronic kidney disease patients^15,16 but not in anephric patients, demonstrating a renal source of the erythropoietin production even in nonfunctioning kidneys. The study of one PDI agent (FG 2216) was halted temporarily after a report of death from fulminant hepatitis, but the other (FG 4592) continues to be studied in a phase 2 clinical trial.^95,96

TAKE-HOME POINTS

• Anemia of renal disease is a common condition that is mainly caused by a decrease in erythropoietin production by the kidneys.
• While anemia of renal disease can be corrected with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies before giving an ESA.
• Anemia of renal disease is associated with significant morbidity such as increased risk of left ventricular hypertrophy, myocardial infarction, and heart failure, and has been described as an all-cause mortality multiplier.
• Unfortunately, the only undisputed benefit of treatment to date remains the avoidance of blood transfusions. Furthermore, the large randomized controlled trials that looked at the benefits of ESA have shown that their use can be associated with increased risk of cardiovascular events. Therefore, use of an ESA in end-stage renal disease should never target a normal hemoglobin levels but rather aim for a hemoglobin level of no more than 11.5 g/dL.
• Use of an ESA in chronic kidney disease should be individualized and is not recommended to be started unless the hemoglobin level is less than 10 g/dL.
• Several newer agents for renal anemia are currently under review. A pegylated form of recombinant human erythropoietin has an extended half-life, and a new and promising category of drugs called HIF stabilizers is currently under study.