Normocytic, normochromic nonregenerative anemia develops in ≈30% to 65% of cats with chronic kidney disease (CKD).1 Anemia affects prognosis, pathophysiology, and quality of life and has been identified as a negative predictor of survival in cats with CKD,2-4 and even relatively small reductions in packed-cell volume (PCV; median, 31% vs 35%) are associated with disease progression.5 Anemia (PCV <27%) has been associated with poor health-related quality-of-life scores in cats with CKD.6 Moderate to severe anemia can cause weakness, lethargy, and inappetence and may therefore affect quality of life.
Anemia triggers potentially detrimental physiologic adaptations, including increased release of norepinephrine, renin, angiotensin II, and aldosterone that can lead to increased heart workload and hypertension and left heart enlargement that could predispose patients to heart failure and fluid overload.1,7,8 Hypoxia may be a key factor in progression of CKD.5,9,10 Anemia therefore has the potential to exacerbate progression of CKD as it compromises oxygen delivery to the kidneys, compounded by loss of vasculature (ie, peritubular capillary rarefaction).5
Anemia should be proactively addressed to avoid negative consequences. Following are the author’s top strategies for treating anemia in cats with CKD.
1. Transfusion
Blood transfusion allows rapid correction of oxygen-carrying capacity and tissue hypoxia and is an important therapeutic approach for severe anemia (PCV <20%), particularly in patients undergoing uremic crisis. Careful donor selection, blood typing, cross-matching (when appropriate), and close monitoring are essential to minimize complications; detailed protocols for donors and recipients are available.11 Transfusion provides a rapid but temporary solution for anemia associated with CKD; a long-term medical strategy is therefore also indicated.
2. Darbepoetin
RBC production is stimulated by the hormone erythropoietin (EPO), which is primarily produced by renal EPO-producing peritubular interstitial cells in the corticomedullary region of the kidney. As kidney disease progresses, the number of hormone-producing cells decreases, and anemia can develop due to lack of EPO. RBC production can be stimulated with recombinant human EPO, including darbepoetin alfa or epoetin alfa. Darbepoetin is a longer-acting form of EPO and, unlike epoetin, has little association with development of anti-EPO antibodies and subsequent pure red cell aplasia.12
Darbepoetin (starting dose, 0.75-1 microgram/kg SC once per week until normal PCV range is reached [typically within 3-4 weeks], then decreased to once every 2-3 weeks to maintain PCV) is currently the treatment of choice, but expense can limit its use.1 Blood pressure and PCV should be checked weekly during the initial treatment period, as hypertension thought to be associated with an overly rapid increase in PCV is the primary adverse effect.1 Other reported adverse effects are rare but include pure red cell aplasia, arthralgia, fever, seizures, polycythemia, and iron deficiency.1
Iron Supplementation
Iron is critical for RBC production, and iron stores can become dysregulated in patients with CKD. Hepcidin is a key mediator in iron metabolism and, when upregulated, works to control iron stores by downregulating the transport protein ferroportin and sequestering iron within enterocytes, hepatocytes, and macrophages.13 Hepcidin is upregulated in response to inflammatory conditions and increases with decreased glomerular filtration rate, as hepcidin is freely filtered through the glomerulus.13 Cats with CKD have increased serum hepcidin concentrations, which are correlated with serum creatinine concentration,13 and thus may not be able to absorb oral iron supplementation or use intracellular stores.
Iron supplementation is recommended when darbepoetin is initiated and every 2 to 3 months until therapy is discontinued, as stimulation of erythropoiesis is associated with high iron demand, and CKD is associated with functional iron deficiency.13,14 Iron injections (iron dextran, 50 mg/cat IM) are typically well tolerated and preferred over oral iron supplementation, which can be bitter (exacerbating poor appetite) and poorly absorbed from the GI tract due to hepcidin upregulation.1
3. Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitors
EPO production is controlled by hypoxia-inducible factor (HIF), a master gene regulator responsible for the physiologic response to reduced tissue oxygenation. HIF activates key genes to restore oxygen balance and protect against cellular damage.10,15 Under normoxic conditions, HIF-alpha is hydroxylated, tagged for disposal, and subsequently degraded by lysosomes.15 Under hypoxic conditions, HIF-alpha cannot be hydroxylated and instead translocates to the nucleus where it combines with HIF-beta and induces EPO transcription.15 HIF and EPO regulation is complex but important to understand because of the recent availability of hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) in veterinary medicine.16 Mechanistically, HIF-PHIs inhibit HIF-alpha hydroxylation, even in normoxic conditions, resulting in increased production of endogenous EPO.17
HIF-PHIs are used in human medicine and have similar, if not better, efficacy and safety compared with erythropoiesis-stimulating agents.17 In veterinary medicine, molidustat (5 mg/kg PO every 24 hours for 28 days, restarted after 7 days if needed) is conditionally approved for use in cats with CKD. In a pilot study of 21 cats with CKD given molidustat or placebo for 28 days, cats that received molidustat had a modest but statistically significant increase in PCV compared with the control group after 21 days of treatment.16 No significant difference was seen between treatment groups at day 28, but this may be attributed to the limited sample size and some cats in the control group being lost from the study. No significant effect was seen on blood pressure. In another study, PCV rapidly increased in clinically normal cats administered molidustat; close monitoring is thus recommended.18 Data collected in cats with CKD over 3 months suggest polycythemia may be less of a concern in diseased patients,16 likely because of counterregulatory mechanisms that can suppress RBC production.
Additional benefits of HIF-PHIs reported in other species include improved iron bioavailability and palliative effects on fibroblast growth factor-23 and blood pressure.19,20 It is unclear whether iron supplementation is necessary when therapy is initiated (as with darbepoetin), as HIF-PHIs are documented to improve iron bioavailability by increasing intestinal absorption of iron and mobilizing stored iron19; however, some human patients continue to require iron supplementation. It can thus be presumed that some cats with CKD may also require continued iron supplementation.20