Treatments for Nonregenerative Anemia Associated with CKD in Cats

Chronic kidney disease (CKD) affects up to 50% of geriatric domestic cats and causes death in up to 17%.¹ Anemia occurs in up to 65% of cats with CKD; prevalence, severity, and need for treatment increase with advancing stages of disease.^2-5 When a cat’s PCV drops below 27%, CKD-associated anemia leads to a reduced quality of life and is also associated with a poorer prognosis and increased risk for CKD progression and cardiovascular disease. CKD-associated anemia has the potential to be associated with cognitive impairment and all-cause mortality.⁶

CKD-Associated Anemia

The anemia resulting from CKD is usually normocytic, normochromic, and nonregenerative and is typically more severe in cats with more advanced stages of CKD. However, in dogs, anemia was found in almost 47% with International Renal Interest Society (IRIS) stage 2 CKD; polychromasia and microcytosis in these dogs might have suggested premature release of immature red blood cells (RBCs) with possibly increased bone marrow activity and disordered iron homeostasis in the earlier stage of CKD.⁷ To the author’s knowledge, similar studies in cats with CKD have not been reported.

The pathogenesis of CKD-associated anemia is complex.⁸ Decreased production of erythropoietin may be the major factor leading to CKD-associated anemia, but other factors are involved. RBCs from patients with CKD have a reduced lifespan and are more fragile in the presence of osmotic stimuli or oxidative stress. Disordered iron hemostasis can occur in patients with CKD due to chronic inflammation and resultant increases in hepcidin, both of which may result from any inflammatory condition, such as periodontal disease, infection, autoimmune disorders, inflammatory bowel disease, or cancer, among other things.⁸ In cats with CKD, concentrations of serum amyloid A are higher, consistent with an inflammatory state.⁹ Deficiencies of minerals (e.g., copper, zinc) or vitamins (e.g., cobalamin, folate) in humans can be associated with CKD and/or dialysis. The complex mineral and bone disorders of CKD also may contribute to development of anemia. According to findings in dogs and humans, therapeutic factors that could potentially contribute to anemia in cats include phosphate binder–associated aluminum overload¹⁰ and renin-angiotensin-aldosterone inhibitors. For appropriate management of a patient with CKD-associated anemia, all of these factors need to be considered.

Treatments for CKD-Associated Anemia

Erythropoiesis-Stimulating Agents

The mainstay for treatment of CKD-associated anemia in cats has been the off-label use of erythropoiesis-stimulating agents (ESAs) such as recombinant human erythropoietin (r-HuEPO) and darbepoetin. There is evidence that cats benefit from such treatment. r-HuEPO has resulted in increased hematocrit in cats with CKD and improved appetite, energy, body condition, alertness, strength, and playfulness.¹¹ Likewise, the use of darbepoetin has been shown to increase hematocrit as well as prolong survival of cats with CKD; however, the target hematocrit was reached in only 56% of cats.¹² Human erythropoietin shares only 80% to 85% amino acid identity with feline erythropoietin; thus, its use is not recommended because antibodies against r-HuEPO and pure red cell aplasia render the benefits short-lived. These effects occur less frequently, if at all, after darbepoetin administration. Other potential adverse events associated with ESA administration to cats include seizures (which may be independent of increased hematocrit or blood pressure), systemic hypertension, persistent anemia, fever, and gastrointestinal disturbances. The frequency of adverse events in larger populations of cats receiving darbepoetin needs to be explored but may be lower than what was reported in the initial study.¹²

An adeno-associated virus vector containing the gene for feline erythropoietin (SB-001) has been developed for cats with CKD-associated anemia and is currently undergoing clinical testing.¹³ In this pilot study, PCV increased in 86% of 23 cats with IRIS stage 2 to 4 CKD during days 28 and 70 after intramuscular injection of SB-001. Adverse events included hypertension and seizures. SB-001 may offer an advantage for some cats because it is given as a single, one-time injection; however, as with other ESAs, it may increase the risk for hypertension.

Although ESAs have been the mainstay of treatment of CKD-associated anemia, approximately 10% to 20% of patients may be resistant,^11-13 possibly resulting from failure to control any of the other factors that contribute to CKD-associated anemia. However, perhaps among the common reasons for lack of response is the disordered iron homeostasis that is associated with CKD. Hepcidin, an iron regulatory protein, inhibits iron absorption and intracellular iron transport, leading to functional iron deficiency. Hepcidin concentrations increase with decreased glomerular filtration rate and inflammatory states, both of which occur in patients with CKD.⁹ These realities necessitate the need for other targets for the management of CKD-associated anemia.

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of orally administered drugs that stimulate endogenous erythropoietin production and improve iron regulation, both of which contribute to a dose-dependent increase in hematocrit.¹⁴ HIF regulates gene expression in response to hypoxia, leading to increased erythropoietin concentrations as well as increased iron absorption and transport, heme synthesis, neoangiogenesis, cell proliferation, and enhanced cell survival. HIF consists of α-subunits (HIF-α) that are sensitive to oxygen and a β-subunit (HIF-β) that is constitutively expressed (also called the ARNT [aryl hydrocarbon receptor nuclear translocator]). HIF-α subunits are rapidly degraded under normoxic conditions, a process that requires HIF–prolyl hydroxylase domain enzymes. When these enzymes are inhibited, either by hypoxic conditions or pharmacologically, they form a heterodimer with HIF-β, leading to increased transcription of the genes that are regulated by HIF, including erythropoietin. In addition, HIF-PHIs decrease hepcidin concentrations and increase intestinal iron absorption.¹⁴

In 2023, the HIF-PHI molidustat (Varenzin-CA1; Elanco, elanco.com) was conditionally approved by the FDA for administration to cats with CKD. In a 28-day pilot study, 50% of 14 cats experienced either an absolute increase in hematocrit of 4% or a 25% increase from baseline; by day 56, treatment was successful for 75% (defined as a > 4 percentage point increase in hematocrit from baseline).¹⁵ The most frequent adverse event was vomiting. Neither hypertension nor seizures developed in any of the cats. A subset of cats was followed for an additional 8 weeks (i.e., the continuation phase), during which they maintained the increased hematocrit and stable mean blood pressure and gained weight.

Molidustat administration to cats is dictated by the parameters associated with the conditional approval, which specifies that 5 mg/kg molidustat can be orally administered once daily for up to 28 days, followed by a mandatory pause of at least 7 days. To ensure that the resultant hematocrit does not exceed the upper limit of the reference range, cats receiving molidustat should be monitored weekly, starting around day 14. If polycythemia develops, administration should be discontinued. If there is no response by 21 days, the cats should be examined for another condition that might be contributing to the anemia before molidustat is restarted. Off-label use, including administration to dogs or to cats that do not have CKD, is prohibited.

HIF-PHIs may prove to be advantageous for patients with CKD because they are given orally, are likely to provide more physiological erythropoietin concentrations, and improve iron homeostasis. By downregulating hepcidin, HIF-PHIs may protect against a negative effect of inflammation. HIF-PHIs may be effective alternatives for patients who are hyporesponsive or resistant to ESAs. Last, if larger studies indicate lack of worsening or induction of hypertension, HIF-PHIs may also be the drug of choice for cats with concurrent hypertension.

Iron

Cats with CKD-associated anemia are at risk for disordered iron homeostasis.⁹ Absolute iron deficiency is defined by reduced iron stores, whereas functional iron deficiency (i.e., iron-restricted erythropoiesis) is defined by adequate iron stores but insufficient iron availability. Most likely, cats with CKD-associated anemia have functional iron deficiency instead of absolute iron deficiency. However, currently available tests of iron stores for cats do not enable clinicians to consistently differentiate between the 2 forms of iron deficiency. Many, but not all, veterinarians will decide to administer iron dextran intramuscularly monthly to manage anemia in cats. Most forms of oral iron carry the risk for adverse gastrointestinal events, the likelihood of which varies with the iron salt being administered, and a comparative study has not been performed in cats. In addition, if hepcidin is increased, iron may not be adequately absorbed from the intestinal tract. Naraquin (Nutramax, naraquin.com) is a new phosphate binder that contains ferric citrate. In theory, ferric citrate may offer an advantage by concurrently supplementing iron and reducing fibroblast growth factor 23, a factor that is increased with total body phosphate overload and believed to exacerbate CKD-associated anemia.

Although not yet studied in cats, HIF-PHI administration to humans with CKD was associated with improved iron regulation and decreased hepcidin concentration.¹⁶ This feature of HIF-PHIs offers a real advantage of this class of drugs compared with traditional ESAs. In theory, reduced hepcidin concentrations would allow for greater absorption of iron from the intestinal tract, potentially aiding in the management of CKD-associated anemia.

Summary

The pathogenesis of CKD-associated anemia includes reduced erythropoietin production as well as iron dysregulation. The main treatment has been off-label use of ESAs, such as r-HuEPO and darbepoetin. Molidustat (Varenzin-CA1) is the first drug conditionally approved for treating nonregenerative anemia associated with CKD in cats. As a member of the class of HIF-PHIs, molidustat may be advantageous for treatment of CKD-associated anemia because it is given orally, may provide more physiological erythropoietin concentrations, may improve iron homeostasis, and may protect against a negative effect of inflammation. Future studies may also indicate that HIF-PHIs are the drug of choice for cats with concurrent hypertension.

Disclosure

Dr. Vaden has received speaking fees from Elanco.