Molidustat in Feline CKD-Associated Anemia: What Clinicians Should Know

Anemia is a frequent complication of chronic kidney disease (CKD) in cats, developing in approximately 30%–65% of affected patients. Reduced erythropoietin (EPO) production is an important contributor. As kidney function declines, the loss of functioning renal EPO-producing cells, along with other disease-associated factors, can impair erythropoiesis^1,2,3,4. 

Recombinant EPO has traditionally been used as an EPO replacement approach in anemic cats. However, complications including iron deficiency, hypertension, arthralgia, fever, seizures, polycythemia, and life-threatening pure red cell aplasia have been reported⁵. These limitations have prompted interest in approaches that stimulate the body's own erythropoietic pathway. 

Molidustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, represents one such approach. 

Understanding the Rationale for Molidustat 

HIF is involved in the regulation of EPO production. Under normal oxygen conditions, HIF is degraded by HIF-PH enzymes. In CKD, changes associated with failing kidneys can contribute to reduced EPO production^2,5,6. 

Inhibiting HIF-PH may therefore stimulate erythrocyte production. Previous administration of molidustat at 5 mg/kg once daily in healthy adult cats resulted in increased EPO concentrations followed by increased hematocrit (HCT), despite normoxic conditions. Molidustat was also well tolerated in those cats. 

This provided the rationale for evaluating the same daily dose in client-owned cats with CKD-associated anemia. 

What Hematological Response Can Be Expected?⁵ 

A multicenter clinical investigation evaluated 21 cats with CKD-associated anemia that received either molidustat or a control product orally once daily for 28 days. HCT was assessed weekly, with treatment success defined as a clinically relevant increase in HCT. 

The response to molidustat developed progressively. Mean HCT in treated cats increased from 23.6% at baseline to 25.2% on Day 7, 25.5% on Day 14, 27.3% on Day 21, and 27.8% on Day 28. The increase from baseline became statistically significant on Day 21 (P < .001). PCV increased significantly earlier, from 22.5% at baseline to 24.7% on Day 14 (P = .02). 

By Day 28, 7/14 molidustat-treated cats met the predefined treatment-success criterion compared with 1/5 cats receiving the control product. However, the difference between groups was not statistically significant. 

For clinical monitoring, these findings suggest that changes in HCT and PCV may become apparent over the first few weeks rather than immediately after treatment begins. 

Individual Response Matters⁵ 

Not every cat demonstrated the same degree of erythropoietic response. Several factors could potentially influence the response in cats with CKD-associated anemia. 

Comorbid conditions causing inflammation, undiagnosed hyperthyroidism, concomitant medications, and insufficient iron stores were identified as possible contributors that could slow or blunt erythropoiesis. CKD staging was also not performed before treatment, so the influence of CKD stage on the response could not be determined. 

For the clinician, this reinforces the value of assessing the individual cat rather than assuming a uniform response. 

Safety and Clinical Monitoring⁵ 

Vomiting was the most frequently reported adverse event, occurring in 6 of 15 cats (40%) receiving molidustat. Seventeen vomiting events were recorded, including nine episodes in one cat that also had decreased appetite during the first week. Decreased appetite was reported in two cats. 

Other reported clinical findings included thrombosis, increased liver enzyme activity, renal failure, dehydration, polyuria/polydipsia, stomatitis, lethargy, cystitis, and other individual events. Three serious adverse events occurred during the 28-day treatment period. 

Mean systemic blood pressure did not show an apparent treatment-related increase. However, different blood-pressure measurement devices were used across sites, and several cats were receiving antihypertensive medications, which may have influenced this observation. 

Practical Clinical Takeaway 

Molidustat may offer an alternative approach to stimulating erythropoiesis in cats with CKD-associated anemia. In the 28-day clinical investigation, HCT and PCV increased significantly from baseline within 14–21 days of daily oral administration at 5 mg/kg. 

For practicing veterinarians, the key message is to view molidustat as a potential erythropoietic option requiring individualized monitoring, rather than assuming that every cat with CKD-associated anemia will respond in the same way. 

References 

1. Chalhoub S, Langston C, Eatroff A. Anemia of renal disease: what it is, what to do and what's new. Journal of feline medicine and surgery. 2011 Sep;13(9):629-40. https://journals.sagepub.com/doi/pdf/10.1016/j.jfms.2011.07.016 

2. Hirota K. HIF-α prolyl hydroxylase inhibitors and their implications for biomedicine: a comprehensive review. Biomedicines. 2021 Apr 24;9(5):468. https://www.mdpi.com/2227-9059/9/5/468 

3. Chalhoub S, Langston CE, Farrelly J. The use of darbepoetin to stimulate erythropoiesis in anemia of chronic kidney disease in cats: 25 cases. Journal of veterinary internal medicine. 2012 Mar;26(2):363-9. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1939-1676.2011.00864.x 

4. Chikazawa S, Dunning MD. A review of anaemia of inflammatory disease in dogs and cats. Journal of Small Animal Practice. 2016 Jul;57(7):348-53. http://labforvets.com/wp-content/uploads/2022/07/A_review_of_anaemia_of_inflammatory_disease_in_dogs_and_cats.pdf 

5. Charles S, Süssenberger R, Settje T, Langston C, Lainesse C. Use of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, in chronic kidney disease-associated anemia in cats. Journal of Veterinary Internal Medicine. 2024 Jan;38(1):197-204. https://academic.oup.com/jvim/article-pdf/38/1/197/66663302/jvim16807.pdf 

6. Flamme I, Oehme F, Ellinghaus P, Jeske M, Keldenich J, Thuss U. Mimicking hypoxia to treat anemia: HIF-stabilizer BAY 85-3934 (Molidustat) stimulates erythropoietin production without hypertensive effects. PloS one. 2014 Nov 13;9(11):e111838. https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0111838&type=printable